causes of cancer research paper

Research on Causes of Cancer

Many things may cause cancer, including exposure to certain substances, specific behaviors, age, and inherited genetic mutations.

Why Research on Causes of Cancer Is Critical to Progress against the Disease

Cancer can be caused by many things, including exposure to cancer-causing substances, certain behaviors, age, and inherited genetic mutations.

Studying the causes of cancer helps researchers understand the process by which normal cells are transformed into cancer cells and identify genetic, environmental, and behavioral risk factors  for cancer . This knowledge can lead to new ways of preventing and treating the disease.

Research on the causes of cancer also creates opportunities to improve public health, not only by identifying cancer risk factors in populations, but also by providing data that regulatory agencies can use to set safety standards or reduce exposure to toxins that are found to be associated with cancer. Findings from this area of research can also be used to inform technological advances, such as safer computed tomography (CT) scans and risk-reducing surgeries.

Researchers use many different approaches to identify potential causes of cancer, from cell-based and animal studies to human observational studies . Research in basic cancer biology can reveal the mechanisms by which biological, chemical, and physical carcinogens initiate and promote cancer. Genetic analyses, such as genome-wide association studies , exome sequencing, and whole-genome sequencing, allow researchers to identify genetic changes that may be associated with cancer risk. Epidemiological approaches—including cohort studies , case-control studies , exposure-assessment studies, family studies, and genomic studies—are used to identify possible causes of cancer and study the patterns of risk in large populations.

Another approach, known as descriptive epidemiology, characterizes trends in cancer incidence and mortality within a given population, between populations over time, and in relation to overall patterns of exposure in populations to yield clues that may point researchers to cancer causes and risk factors. This type of research can also identify emerging trends in cancer incidence.

Opportunities in Research on Causes of Cancer

NCI Research and the National Cancer Plan

NCI supports a broad variety of research that aligns with the goals of the National Cancer Plan. Read about the plan and explore each goal.

Advances in technology are improving how we determine and measure risk factors, enabling researchers to store and access findings in online databases, and allowing teams of investigators worldwide to pool data on an unprecedented scale. Multidisciplinary research teams are increasingly common and often include a range of experts, including epidemiologists, physicians, computational biologists, statisticians, oncologists, toxicologists, and geneticists.

Technological advances have also led to more accurate studies of substances in the environment suspected of causing cancer. Developing devices that can accurately measure environmental exposures and biochemical assays in biologic specimens that might be associated with cancer could improve researchers’ ability to identify cancer-causing agents.

Identifying people at highest risk of cancer, such as those with an inherited susceptibility to cancer or those who have been exposed to carcinogens, creates opportunities to develop risk prediction models and allows health providers to focus prevention and screening interventions on those most likely to benefit.

Challenges in Research on Causes of Cancer

Demonstrating cause-and-effect relationships in population studies  examining potential cancer risk factors is a challenge because there are often many possible explanations for observed associations between a risk factor and cancer. Establishing cause and effect can require studying a large group of people and/or following individuals over many months or years.

Rare cancers and uncommon exposures, in particular, present challenges for researchers studying the causes of cancer. New statistical methods may be needed to improve the analysis of datasets of all sizes from these studies.

Methodologic issues also pose challenges to determining whether substances in the environment, even those known to cause cancer in animals, actually cause cancer in humans.

Studying the Impact of Total Diet on Cancer Risk

Researchers are changing how they assess the effect of diet on cancer, health.

When studying certain exposures, such as dietary exposures, identifying which component is associated with an increased or decreased risk of cancer can also be a challenge.  Retrospective studies have additional limitations, such as participants’ inability to accurately remember and report past exposures or exposure levels.

There is a continual need for new and improved techniques for measuring risk factors and exposures to potential causes of cancer. For example, studies that estimate radiation exposures among an exposed population must also quantify the uncertainties inherent to those estimates.

To identify cancer causes and risk factors that may be experienced by only a portion of the population, very large studies may be needed to have the statistical power required to establish an association.

Investigating interactions between genes and environmental exposures that have been associated with cancer is a challenge because some of these studies involve enormous data sets and require sophisticated computational analyses. Once a causative agent has been identified, another challenge is figuring out how to reduce a person’s exposure or ameliorate its harmful effects.

Although genome-wide association studies can point to chromosomal regions associated with cancer risk in certain populations, additional studies and analyses are needed to identify the specific genetic changes involved and to understand how they play a role in the development of cancer.

NCI's Role in Research on Causes of Cancer

NCI Fiscal Year 2025 Professional Judgment Budget Proposal

Each year, NCI prepares a professional judgment budget to lead progress against cancer.

NCI funds and conducts research on the causes of cancer. The intramural research program allows the institute to conduct studies that require long-term, sustained support and provides NCI with the flexibility to redirect resources, when necessary, to respond quickly to emerging public health concerns.

NCI and NCI-funded researchers aim to understand the exposures and risk factors that cause cancer, as well as the genetic basis for cancer development.

Studies conducted by the  NCI Cohort Consortium , for example, seek to identify factors (including environmental, lifestyle, and genetic) that may influence cancer risk. The consortium is a partnership between intramural and extramural investigators that pools the large quantity of data and biospecimens necessary to conduct a wide range of cancer studies. The consortium consists of investigators responsible for more than 50 cohorts that include more than 7 million people in the United States and around the globe.

Intramural and extramural investigators also seek to identify ways to translate these research findings into tangible benefits to prevent cancer, identify and monitor those at risk, and develop clinical and public health interventions.

Environmental and Behavioral Risk Factors

NCI’s Division of Cancer Epidemiology and Genetics (DCEG)  and the Epidemiology and Genomics Research Program in NCI’s Division of Cancer Control and Population Sciences (DCCPS) conduct and fund research to identify and evaluate a range of exposures and risk factors that may be associated with cancer, including:

• substances in the environment and workplace, such as chemicals and air and water pollutants. For example, the Diesel Exhaust in Miners Study found that heavy exposure to diesel exhaust is associated with an increased risk of lung cancer.
• infectious agents, such as viruses and bacteria. For example, NCI investigators have studied human papillomavirus (HPV) over many decades , helping to define its role in the development of cervical and other cancers. This work has helped improve screening approaches and demonstrated the effectiveness of the HPV vaccine.
• radiation, both ionizing and nonionizing. For example, DCEG investigators are involved in several studies of cancer incidence among children undergoing CT scans .
• pharmaceutical agents and exogenous and endogenous hormones. For example, researchers involved in the DES Follow-Up Study are following women and their daughters, sons, and granddaughters who were exposed to diethylstilbestrol (DES) for adverse health effects, including cancer.
• behavioral and lifestyle factors, such as diet and nutrition, tobacco use, alcohol use, energy balance , physical activity, obesity, cancer screening behavior, and sun protection. For example, DCCPS’s Behavioral Research Program funds the Transdisciplinary Research on Energetics and Cancer (TREC) Centers .
• immune system status and inflammation. For example, the DCEG  HIV/AIDS Cancer Match Study provides population-based data on cancer risk and trends among HIV-infected people in the United States.

A key question of great research interest is the role of environmental agents in causing breast cancer. In May 2021, NCI and the National Institute of Environmental Health Sciences held a virtual scientific meeting, Breast Cancer and the Environment: Controversial and Emerging Exposures , to identify new research opportunities and approaches to address knowledge gaps.

DCEG researchers and those funded by DCCPS are also studying risks of second primary cancers . Nearly one in five cancers occurs in an individual with a previous diagnosis of cancer, and these second cancers are a leading cause of morbidity and mortality among cancer survivors. Research on treatment, lifestyle, environmental, and medical history factors associated with second cancers is ongoing, as is research on genetic susceptibility to second cancers.

Genetic Factors

AMBRA1 Protein Found to Be an Important Tumor Suppressor

Discovery points to new possibilities for future cancer treatments.

NCI and NCI-funded investigators are also studying genetic factors that may predispose individuals to cancer and gene–environment interactions in cancer risk using approaches such as genome-wide association studies and whole genome scans.

Changes in an individual’s genes, including gene mutations, genetic modifiers, and polymorphisms , can alter his or her lifetime risk of cancer. To explain the genetic factors that influence a person’s risk for cancer, NCI and NCI-funded investigators are:

• conducting human genetic studies to identify and validate key susceptibility genes and their modifiers using knowledge gained from gene expression profiles and protein “fingerprints”
• identifying genetic and environmental factors that influence the cancer epigenome (i.e., chemical modifications to DNA that do not involve DNA sequence changes)
• defining the role of inherited or acquired genetic alterations, in combination with lifestyle factors and environmental exposures (such as radiation and chemicals), as important determinants of an individual’s cancer susceptibility
• identifying new tumor suppressor genes and oncogenes, and elucidating their mechanisms of action
• identifying, mapping, and characterizing genes and chromosome regions that are involved in tumor initiation and progression

For example, investigators in DCEG’s Radiation Epidemiology Branch are partnering with investigators from the Childhood Cancer Survivor Study to conduct a genome-wide association study of second cancers in childhood cancer survivors.

NCI researchers are also studying a range of hereditary cancer syndromes that predispose affected individuals and their family members to cancer. These include inherited bone marrow failure syndromes , Li-Fraumeni syndrome , DICER1 syndrome , familial melanoma , and others. Studies of people with hereditary cancer syndromes help researchers understand the underlying biology of cancer risk and develop ways to improve the management of these disorders.

Such studies may also, indirectly, provide insights into the genetic basis for noninherited, or sporadic, forms of cancers. That was the case with research on familial kidney cancer  by W. Marston Linehan, M.D., of NCI's Center for Cancer Research (CCR).

DCEG and CCR investigators are also studying cancer predisposition syndromes such as RASopathies, conditions caused by changes in genes in the RAS/MAPK pathway. People with RASopathy syndromes have a higher risk of developing cancer and may have developmental issues and cognitive and congenital disabilities. The RASopathies study team aims to understand how genetics and environmental factors contribute to cancer development in patients with these syndromes. The team also hopes to learn how to better screen for, detect, and treat these syndromes using these data.

How Exposures and Risk Factors Act

NCI supports and conducts research to understand the mechanisms by which external exposures and risk factors induce and promote cancer.

NCI’s Division of Cancer Biology (DCB) supports research investigating the role of biological agents and host factors that contribute to cancer. DCB’s Cancer Immunology, Hematology and Etiology Branch , for example, funds research on the role of the microbiome in cancer development and the influence of aging on cancer susceptibility. DCB also supports research to understand mechanisms by which carcinogens initiate and promote tumor development.

CCR researchers are trying to elucidate mechanisms that influence tumor initiation, promotion, and progression, including those associated with lifestyle, the environment, inflammation, the immune system, viruses, and host-tumor interaction.

NCI’s Office of HIV and AIDS Malignancy (OHAM) coordinates and oversees NCI research programs that focus specifically on HIV/AIDS and AIDS-associated cancers. For example, OHAM’s AIDS and Cancer Specimen Resource is a biorepository for HIV-infected human biospecimens that serves as a resource for investigators conducting basic research in the pathogenesis of AIDS-related malignancies.

Lung cancer

Affiliations.

• 1 Peter MacCallum Cancer Centre, Melbourne, VIC, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, VIC, Australia.
• 2 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
• 3 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA. Electronic address: [email protected].
• PMID: 34273294
• DOI: 10.1016/S0140-6736(21)00312-3

Lung cancer is one of the most frequently diagnosed cancers and the leading cause of cancer-related deaths worldwide with an estimated 2 million new cases and 1·76 million deaths per year. Substantial improvements in our understanding of disease biology, application of predictive biomarkers, and refinements in treatment have led to remarkable progress in the past two decades and transformed outcomes for many patients. This seminar provides an overview of advances in the screening, diagnosis, and treatment of non-small-cell lung cancer and small-cell lung cancer, with a particular focus on targeted therapies and immune checkpoint inhibitors.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Publication types

• Research Support, Non-U.S. Gov't
• Carcinoma, Non-Small-Cell Lung / diagnosis*
• Carcinoma, Non-Small-Cell Lung / therapy*
• Lung Neoplasms / diagnosis*
• Lung Neoplasms / therapy*
• Small Cell Lung Carcinoma / diagnosis*
• Small Cell Lung Carcinoma / therapy*

Watch Now : CRI’s Patient Immunotherapy Summit

Immune to Cancer: The CRI Blog

What are the causes of cancer?

There are an estimated 18.1 million new cancer cases globally, and cancer remains the second-leading cause of death in the United States, where more than 1.7 million people are diagnosed with cancer every year. Cancer is often discussed as if it’s one thing. But while unrestrained growth is the common denominator, cancer can develop in a variety of different ways, due to a variety of different factors. Some we inherit, and others we are exposed to throughout our lives. It can be categorized into hundreds of different diseases based on the cells in which it arises. And when each patient’s genetic background is taken into account, no two cases are identical.

To save more lives from cancer, therefore, it will be necessary to address this complexity. Through basic research into cancer biology and immunology, we can improve our understanding of how cancer develops and how it interacts with the immune system. In this way, it could enable us to discover new, more effective ways to treat cancer.

When does cancer occur?

Cellular definition of cancer.

Cancer begins when cells acquire the ability to grow uncontrollably and ultimately invade and damage the body’s normal tissues. Cancer development happens in multiple stages, from precancerous changes to malignant tumors. However, not all cancers form tumors, and different cancers can develop at different rates. Sometimes cancer cells spread from their original site to other places in the body through the bloodstream or lymphatic system—a process called metastasis .

Where does cancer occur?

Cancer’s point of origin.

Cancer can affect many different parts of the body, from the skin, bone, blood vessels, and muscle, to the lungs, kidneys, and many other organs. Cancer can also affect the immune system, which plays a key role during both the development and progression of cancer.

Can you inherit cancer?

Genetic causes of cancers.

Genes are segments of DNA located on chromosomes, and can mutate over time to become cancerous. These mutations can result from a variety of causes, including diet and lifestyle choices as well as exposure to certain environmental factors. Overall, only 5 to 10 percent of all cancers are genetically inherited, although these are the cancers that tend to occur earlier in life.

One such inheritable genetic disorder that is associated with increased cancer risk is Lynch syndrome , which prevents cells’ ability to repair their DNA when damage occurs. This can lead to cancers of the colon and uterus at an early age. Another such genetic factor is the BRCA family of genes, certain forms of which have been linked to breast and ovarian cancer .

Today, scientists and clinicians are using and developing new tests to search for biomarkers , which can help determine risks and appropriate treatment options based on an individual patient’s genetic profile.

Does behavior or lifestyle cause cancer?

Behavioral causes of cancer.

There are a number of behavioral factors that can lead to genetic mutations and, as a result, lead to the development of cancer.

• Tanning (excessive exposure to ultraviolet light)
• Diet (red, processed meats)
• Unsafe sex (leading to viral infection)
• Inflammatory conditions, such as ulcerative colitis or obesity

An example of a behavioral risk factor is smoking, which can lead to lung cancer, or excessive exposure to the sun’s ultraviolet (UV) rays, which can cause skin cancer. Some dietary choices, including red meat and alcohol, have also been linked to certain types of cancer, while obesity is associated with higher rates of cancer as well, a link that CRI investigators Harvard Medical School’s Lydia Lynch, PhD , and University of California, San Diego’s Zhenyu Zhong, PhD , are independently exploring further. One’s diet can also affect the bacteria that reside within our intestines, known as the gut microbiome, and recent research by scientists, such as Johns Hopkins University’s Cynthia Sears, MD , have revealed that certain bacteria can impact the likelihood of colorectal cancer development as well as patient responsiveness to treatment with immunotherapy.

Can where you live or work cause cancer?

Environmental causes of cancer.

Exposure to certain factors in the environment, such as chemicals like asbestos and benzene, as well as talcum powder and various sources of radiation (including excessive X-rays), can also cause cancer. These substances capable of damaging DNA and triggering cancer are referred to as carcinogens.

• Excessive sun exposure (UV)
• Chemical carcinogen exposure
• High-dose chemotherapy and radiation (mainly in children being treated for existing cancers)
• Hormonal drugs
• Immune-suppressing drugs (taken by transplant recipients)
• Radioactive materials, e.g., radon

In addition to other factors associated with aging and senescence, older individuals are more likely to have had exposure to environmental risk factors and are therefore diagnosed with cancer much more frequently than young people. When it comes to children with cancer, new immunotherapy approaches are providing for the possiblity of treating them not only more effectively, but also without some of the damaging side effects that can accompany conventional treatments.

Do viruses or bacteria cause cancer?

Viral and bacterial causes of cancer.

Theories surrounding bacterial causes of cancer date back over 100 years, put forth by the Father of Cancer Immunotherapy, Dr. William B. Coley . A person’s behavior and surroundings can expose them to bacteria and viruses known to cause cancer.

• Human papillomavirus (HPV)
• Hepatitis B (HBV) and hepatitis C (HCV) viruses
• Epstein–Barr virus (EBV)
• Human T-lymphotropic virus
• Kaposi's sarcoma-associated herpesvirus (KSHV)
• Merkel cell polyomavirus
• Helicobacter pylori

Exposure to the B and C strains of the hepatitis virus can result in liver cancer, and sexual transmission of certain strains of the human papillomavirus (HPV) can result in cervical cancer, anal and penile cancers, and several head and neck cancers .

A vaccine that protects against hepatitis B virus has been available since 1982; in fact, this vaccine was the first preventive cancer vaccine in existence. The Cancer Research Institute funds research into both preventive and therapeutic cancer vaccines, including Dr. Ian Frazer’s groundbreaking work on the development of Gardasil, the first preventive vaccine against cervical cancer.

Bacteria and viruses can also be engineered to fight cancer on our behalf. Oncolytic virus therapy uses modified viruses to infect tumor cells and cause them to produce chemicals that signal danger to the immune system before self-destructing. Antibodies that target cancer antigens can be engineered through a process called phage display, in which a bacteriophage (a virus that infects bacteria) can be used to evolve new proteins.

Although there are number of elements at play in the development of cancer, the treatments at our disposal are constsntly improving and adapting as new research provides insight into various risk factors. Learn more about why immunotherapy research matters and how CRI’s innovative approach has shaped the progress of cancer treatments . You can contribute to continued breakthroughs in cancer research and treatment options by making a donation to CRI today .

Let's spread the word about Immunotherapy! Click to share this page with your community.

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• 25 year trends in...

25 year trends in cancer incidence and mortality among adults aged 35-69 years in the UK, 1993-2018: retrospective secondary analysis

Linked editorial.

Cancer trends in the UK

• Related content
• Peer review
• Jon Shelton , head of cancer intelligence 1 ,
• Ewa Zotow , visiting lecturer (statistics) 2 ,
• Lesley Smith , senior research fellow 3 ,
• Shane A Johnson , senior data and research analyst 1 ,
• Catherine S Thomson , service manager (cancer and adult screening) 4 ,
• Amar Ahmad , principal statistician 1 ,
• Lars Murdock , data analysis and research manager 1 ,
• Diana Nagarwalla , data analysis and research manager 1 ,
• David Forman , visiting professor of epidemiology 5
• 1 Cancer Research UK, London, UK
• 2 University College London, London, UK
• 3 Leeds Institute of Clinical Trials Research, University of Leeds, Leeds, UK
• 4 Public Health Scotland, Edinburgh, UK
• 5 Faculty of Medicine and Health, University of Leeds, Leeds, UK
• Correspondence to: J Shelton jon.shelton{at}cancer.org.uk
• Accepted 19 January 2024

Objective To examine and interpret trends in UK cancer incidence and mortality for all cancers combined and for the most common cancer sites in adults aged 35-69 years.

Design Retrospective secondary data analysis.

Data sources Cancer registration data, cancer mortality and national population data from the Office for National Statistics, Public Health Wales, Public Health Scotland, Northern Ireland Cancer Registry, NHS England, and the General Register Office for Northern Ireland.

Setting 23 cancer sites were included in the analysis in the UK.

Participants Men and women aged 35-69 years diagnosed with or who died from cancer between 1993 to 2018.

Main outcome measures Change in cancer incidence and mortality age standardised rates over time.

Results The number of cancer cases in this age range rose by 57% for men (from 55 014 cases registered in 1993 to 86 297 in 2018) and by 48% for women (60 187 to 88 970) with age standardised rates showing average annual increases of 0.8% in both sexes. The increase in incidence was predominantly driven by increases in prostate (male) and breast (female) cancers. Without these two sites, all cancer trends in age standardised incidence rates were relatively stable. Trends for a small number of less common cancers showed concerning increases in incidence rates, for example, in melanoma skin, liver, oral, and kidney cancers. The number of cancer deaths decreased over the 25 year period, by 20% in men (from 32 878 to 26 322) and 17% in women (28 516 to 23 719); age standardised mortality rates reduced for all cancers combined by 37% in men (−2.0% per year) and 33% in women (−1.6% per year). The largest decreases in mortality were noted for stomach, mesothelioma, and bladder cancers in men and stomach and cervical cancers and non-Hodgkin lymphoma in women. Most incidence and mortality changes were statistically significant even when the size of change was relatively small.

Conclusions Cancer mortality had a substantial reduction during the past 25 years in both men and women aged 35-69 years. This decline is likely a reflection of the successes in cancer prevention (eg, smoking prevention policies and cessation programmes), earlier detection (eg, screening programmes) and improved diagnostic tests, and more effective treatment. By contrast, increased prevalence of non-smoking risk factors are the likely cause of the observed increased incidence for a small number of specific cancers. This analysis also provides a benchmark for the following decade, which will include the impact of covid-19 on cancer incidence and outcomes.

Introduction

The availability of comprehensive cancer registration data across the UK since 1993 makes comparison of cancer incidence and mortality trends over 25 years possible. We examined UK trends in cancer incidence and mortality for men and women, aged 35-69 years, for all cancers combined and for the most common sites (or site groups) of cancer between 1993 and 2018.

This study focuses on the 35-69 years age group because cancer trend data are more reliable and easier to interpret in this age range. 1 Diagnostic accuracy is better in this age range than in older patients who have a greater proportion of clinical and uncertain diagnoses, as evidenced by the relatively low proportion of microscopically verified tumours, 2 especially in the earlier part of the period analysed. By the age of 35 years, the pattern of cancer broadly represents the usual adult profiles because specific cancers that are observed in childhood, adolescence, and young people would not impact on the overall pattern. Trends in the 35-69 years age group are also reflective of causal factors in the more recent and medium term past rather than in the longer term and, therefore, will be more indicative of future patterns of cancer in the older populations.

This time period has also seen the introduction of three population screening programmes across the UK, which have affected trends by diagnosing some cancers at an earlier stage, preventing cancers, but also had the potential for diagnosing some cancers that would not have otherwise caused harm to the individual, particularly breast cancer. 3 4 Cervical smear tests have been used since the 1960s and the national screening programme was introduced in 1988, with over 85% coverage of the target population (women and people with a cervix aged 25-64 years) in the UK by 1994. 5 The breast screening programme was introduced in 1988 and covered all UK countries by the mid-1990s, with women aged 50-70 years being invited. 6 The bowel screening programme was introduced from 2006 and took a number of years to reach full roll-out. Currently, people aged 60-74 across England, Wales, and Northern Ireland, and 50-74 for Scotland are eligible. Prostate specific antigen testing is not part of the national screening programme. Anyone older than 50 years with a prostate can request a prostate specific antigen test from their family doctor (general practitioner).

The past 25 years have seen differing trends in cancer risk factors, with the two most important risk factors displaying trends in opposing directions. In one direction, smoking prevalence is reducing due to introductions of tax rises on tobacco products, further advertising bans, and smokefree policies, including education and encouraging quitting, and, in the other direction, the proportion of the population classified as overweight or obese is increasing, of which diet and exercise contribute to, as well as being independent risk factors for cancer. 7

Cancer registration data are currently collected by four national registries in the UK. These organisations collect detailed information on newly diagnosed primary tumours, referred to as registrations. Prior to 2013, cancer registrations in England were collected by eight regional registries and compiled by the Office for National Statistics, 8 with these regional registries producing complete population coverage for England since 1971. 9 Cancer Research UK aggregate these data from the UK registries, with incidence, mortality, and corresponding national population data provided by the Office for National Statistics, Public Health Wales, 10 Public Health Scotland, 11 the Northern Ireland Cancer Registry, 12 NHS England, 13 and the General Register Office for Northern Ireland. 14 Coding of cancer registrations is consistent between countries of the UK, using internationally accepted codes from the International Classification of Diseases 10th revision (ICD-10) and collaboration through the UK and Ireland Association of Cancer Registries. 15

Cancer sites (for single sites) or site groups (with multiple sites, such as oral) included in these analyses were selected as the most common causes of cancer incidence or death. These cancer sites are: all cancers combined (excluding non-melanoma skin cancer for incidence) (C00-C97, excluding C44); bladder (C67); bowel (C18-C20); brain and central nervous system (C70-C72, C75.1-C75.3, D32-D33, D35.2-D35.4, D42-D43, D44.3-D44.5); breast (women only) (C50); cervix (C53); Hodgkin lymphoma (C81); kidney (C64-C66, C68); larynx (C32); leukaemia (C91-C95); liver (C22); lung (C33-C34); melanoma skin(C43); mesothelioma (C45); myeloma (C90); non-Hodgkin lymphoma (C82-C86); oesophagus (C15); lip, oral cavity, and pharynx (oral) (C00-C06, C09-C10, C12-C14); ovary (C56-C57.4); pancreas (C25); prostate (C61); stomach (C16); testis (C62); and uterus (C54-C55). In addition, sex specific all cancer groups are also presented without breast and prostate cancers to inspect the overall trends in the absence of the most common cancer site for each sex. Sex is reported as recorded by the cancer registries at the time of registration. Mesothelioma was a new specific code introduced in ICD-10 and no reliable mortality data are available for this site before 2001, hence, we have not included this type of cancer prior to then. Non-malignant brain and central nervous system codes (ICD-10 D codes) are included despite their benign nature because they can cause mortality due to their location in the cranial cavity. The codes included for the brain and central nervous system have been chosen following clinical engagement and discussion with cancer registries across the UK. Non-melanoma skin cancer is excluded for incidence data because of the lack of completeness in the recording of these cancers and therefore unreliability of the data; this process is standard practice among UK cancer registries. 16 A proportion of non-melanoma skin cancer cases can be diagnosed and treated within primary care and have not consistently been captured within cancer registration data. 17

To overcome yearly variation for sites with low numbers of cases, we calculated three-year rolling average age standardised rates per 100 000 population. 18 These rates were based on the European standard population 2013 for men and women separately for each cancer site or site group for both incidence and mortality, restricted to the 35-69 years age group. 19

The estimated annual percentage change is commonly computed using a generalised linear regression model with Gaussian or Poisson link function. 18 20 In this analysis, a generalised linear model was performed with quasi-Poisson link function as overdispersion is very common when modelling rates and count data. 21 The outcome was the age standardised cancer (incidence or mortality) rate per 100 000 and the independent variable was the period variable, which was defined as the three year period for each data point, starting from 1993-95 and ending with 2016-18. Estimated annual percentage change was estimated as (exp (β^−1)' 100, where β^ is the estimated slope of the period variable, with corresponding 95% confidence interval, which is derived from the fitted quasi-Poisson regression model. 22 The determination of trends was based on the following criteria: firstly, an increasing trend was identified when the estimated annual percentage change value and its 95% confidence interval were greater than zero. This value suggests a statistically significant increase in the age standardised rate over time. Secondly, a decreasing trend was indicated when both the estimated annual percentage change value and its 95% confidence interval were less than zero, signifying a statistically significant decline in the age standardised rate over the period considered. Finally, in cases where these conditions were not met, the age standardised rate was concluded to have remained relatively stable. This designation means that no significant change in the age standardised rate over the period examined was noted. These criteria ensure a thorough and precise interpretation of the estimated annual percentage change values and their corresponding trends. These analyses were carried out for each sex and site or site group separately. Statistical analysis was performed using R version 4.0.2. 23

Patient and public involvement

This work uses aggregated and non-identifiable routine data that have been provided by patients and collected by the health services of the UK as part of their care and support. Given the aggregated nature of the data, attempts to identify or involve any of the patients whose data are included is not possible nor permitted. Although patients and the public were not involved in the design and conduct of this research, the aim of this research is to provide an assessment of trends in cancer incidence and mortality and the impacts of treatment and policy changes to improve outcomes for cancer patients across the UK. Dissemination to the public will include a press release and a summary published online, written using layman’s terms, and a webinar to discuss the results.

Table 1 and table 2 show the percentage of all newly diagnosed cancer cases and deaths by age group in 1993 and 2018. For male registrations, around 43% of all registrations were in the 35-69 years age group in 1993 and 2018, while for female registrations, between 47% and 48% of all registrations were in this age group in 1993 and 2018, respectively. For mortality, around 40% of male cancer deaths occurred in the 35-69 years age group in 1993 and this value was lower at 30% in 2018. For female cancer deaths, a slightly smaller reduction was noted, from 38% in the 35-69 years age group in 1993 to 31% in 2018.

Number of newly diagnosed cancer cases (% of total) in the UK for all cancers, excluding non-melanoma skin cancer, (ICD-10 C00-C97 excluding C44) by sex and age group in 1993 and 2018

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Number of deaths (% of total) in the UK for all cancers, (ICD-10 C00-C97) by sex and age group in 1993 and 2018

Figure 1 shows the number of newly diagnosed cancer cases and deaths in the 35-69 years age group between 1993 and 2018 by sex. Across the UK, of cancer registrations in 2018, 83% were from England, and 5.1% from Wales, 9.2% from Scotland, and 2.7% from Northern Ireland; for deaths in 2018, 81.4%, 5.3%, 10.4%, and 2.9% were from England, Wales, Scotland, and Northern Ireland, respectively. These proportions remained relatively stable over the study period. For men, the number of cancer registrations increased by 57% from 55 014 cases registered in 1993 to 86 297 cases registered in 2018, while for women, cases increased by 48% from 60 187 in 1993 to 88 970 in 2018. The rate of increase in the number of cases of cancer was more marked between 2003 and 2013 for both sexes than in other time periods in the study.

Number of newly diagnosed cancer cases and deaths in the UK for all cancers, excluding non-melanoma skin cancer for incidence (International Classification of Diseases (10th revision) codes C00-C97 (excluding C44 for incidence)), men and women, 35-69 years, 1993 to 2018. An interactive version of this graphic is available at https://bit.ly/4acPDjP

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The number of cancer deaths in men and women aged 35-69 years decreased: by 20% in men from 32 878 in 1993 to 26 322 deaths in 2018 and by 17% in women from 28 516 in 1993 to 23 719 deaths in 2018. The main decrease in the number of deaths per year occurred before the year 2000 ( fig 1 ) with a decrease of 14% in males and 11% in females between 1993 and 2000. Since 2000, the number of deaths each year in both men and women has remained fairly constant ( fig 1 ).

Table 3 , table 4 , figure 2 and figure 3 , and figure 4 and figure 5 show the trends over time in both incidence and mortality rates by sex and cancer site or site group. The tables only include specific age standardised incidence and mortality rates for the first (1993-95) and last (2016-18) period to give an indication of the change over the 25 year period. The trends in incidence and mortality age standardised rates for all years are shown in the figures. Figure 6 and figure 7 show the age adjusted average annual percentage change in the rates. Between 1993-95 and 2016-18, the age standardised incidence rate for all cancers (excluding non-melanoma skin cancer) increased slightly in men and women with age adjusted annual increases of 0.8% for both sexes. The trends in prostate and breast cancer, as the two largest cancer sites in men and women, respectively, substantially contribute to the overall all sites trends for cancer incidence. Figure 3 shows the trends for each sex without the largest cancer site. In contrast to the male age standardised incidence rate for all cancers, which showed a general increase, the incidence trend for men for all cancers excluding non-melanoma skin and prostate cancer, showed a decrease before 2000, but very little change in the following period. For women, an increase in age standardised incidence rates for all cancers excluding non-melanoma skin and breast cancer is still observed but the rate of increase is lower, at 0.7% per annum on average, over the 25 year period. Over the same period reductions in age standardised mortality for all cancers, including non-melanoma skin cancer, were −2.0% per year in men and −1.6% in women. Exclusion of prostate cancer from the mortality trends for men had a negligible effect on the average annual percentage change. For women, the exclusion of breast cancer from mortality trends led to a smaller decrease in mortality of −1.3% per annum.

Age standardised* incidence and mortality rates in 1993-95 and 2016-18 and percentage change by cancer type, men aged 35-69 years, UK

Age standardised* incidence and mortality rates in 1993-95 and 2016-18 and percentage change by cancer type, women aged 35-69 years, UK

European 2013 population age standardised incidence and mortality rates in the UK for all cancers, 19 excluding non-melanoma skin cancer for incidence (International Classification of Diseases (10th revision) codes C00-C97 excluding C44 for incidence), men and women, 35-69 years, 1993-95 to 2016-18. An interactive version of this graphic is available at https://bit.ly/4a484aE

European 2013 population age standardised incidence and mortality rates in the UK for all cancers in men and women aged 35-69 years during 1993-95 to 2016-18, 19 excluding non-melanoma skin cancer for incidence, and breast cancer in women and prostate cancer in men were excluded for incidence and mortality (International Classification of Diseases (10th revision) codes C00-C97 excluding C44 for incidence, C50, C61). An interactive version of this graphic is available at https://bit.ly/3vakQoX

European 2013 age standardised incidence and mortality rates by year, 19 in the UK, for men and women aged 35-69 years from 1993-95 to 2016-18, by cancer site. An interactive version of this graphic is available at https://bit.ly/49a6ovn

Relative European 2013 age standardised incidence and mortality rates by year, 19 in the UK, for men and women aged 35-69 years from 1993-95 to 2016-18 (the reference year is 1993-95=100), by cancer site. CNS=central nervous system. An interactive version of this graphic is available at https://bit.ly/3PiKGOk

Average annual percentage change in incidence and mortality rates, in the UK, for men aged 35-69 years from 1993-95 to 2016-18 by cancer site. An interactive version of this graphic is available at https://bit.ly/3wMR6yU

Average annual percentage change in incidence and mortality rates, in the UK, for women aged 35-69 years, from 1993-95 to 2016-18, by cancer site. An interactive version of this graphic is available at https://bit.ly/3v0QdT7

Incidence rates varied over time across the different cancer sites and site groups. The largest average annual percentage increases over time for cancer incidence rates for men aged 35-69 years were for cancers of the liver (4.7%), prostate (4.2%), and melanoma skin cancer (4.2%). Increases of 1% or more per annum were also seen for oral cancer (3.4%), kidney cancer (2.7%), myeloma (1.6%), Hodgkin lymphoma (1.5%), testicular cancer (1.3%), non-Hodgkin lymphoma (1.0%), and leukaemia (1.0%). The largest annual decreases over the two decades were seen for stomach (−4.2%), bladder (−4.1%), and lung cancers (−2.1%), with decreases of more than 1% per annum also observed for mesothelioma (−1.9% from 2001 onwards) and laryngeal cancer (−1.5%).

For women, the largest average annual percentage increases in incidence rates were noted for liver (3.9%), melanoma skin (3.5%), and oral (3.3%) cancers with increases in incidence of more than 1% per annum also observed for kidney (2.9%), uterus (1.9%), brain and central nervous system cancers (1.8%), Hodgkin lymphoma (1.6%), myeloma (1.1%), and non-Hodgkin lymphoma (1.0%). The largest annual decreases were reported for bladder (−3.6%) and stomach (−3.1%) cancers while the only other site showing a decrease of more than 1% per annum was cervical cancer (−1.3%). Although breast cancer represents the largest individual cancer site for women and therefore plays a large part in all cancer trends, the average annual increase was only 0.9%. All the incidence changes mentioned, for both men and women, and most incidence changes shown in table 3 and table 4 and in figure 6 and figure 7 were statistically significant (P<0.05) even when the size of change was relatively small.

Mortality rates mainly decreased over time in both sexes. For men, the cancer sites that showed average annual percentage reductions in mortality rates of more than 1% per annum were stomach (−5.1%), mesothelioma (–4.2% from 2001), bladder (–3.2%), lung (–3.1%), non-Hodgkin lymphoma (–2.9%), testis (–2.8%), Hodgkin lymphoma (–2.6%), bowel (–2.5%), larynx (–2.5%), prostate (–1.8%), myeloma (–1.7%), and leukaemia (–1.6%). Only liver (3.0%) and oral (1.1%) cancers showed an average annual increase in mortality of 1% or more with melanoma skin cancer (0.3%) the only other site showing an increase. For women, the cancer sites with average annual decreases in mortality per year of 1% or more were stomach (–4.2%), cervix (–3.6%), non-Hodgkin lymphoma (–3.2%), breast (–2.8%), Hodgkin lymphoma (–2.8%), ovary (–2.8%), myeloma (–2.3%), bowel (–2.2%), leukaemia (–2.1%), larynx (–2.0%), mesothelioma (–2.0% since 2001), bladder (–1.6%), oesophagus (–1.2%), and kidney (1.0%). As with men, liver (2.7%) and oral (1.2%) cancers showed average annual increases of more than 1%, in addition to uterine cancer (1.1%). For both men and women, the mortality changes mentioned previously and most mortality changes shown in table 3 and table 4 and in figure 6 and figure 7 were statistically significant (P<0.05), even when the size of change was relatively small.

Principal findings

The most striking finding in this analysis of UK cancer trends among the 35-69 years age group is the substantial decline in cancer mortality rates observed in both sexes (37% decline in men and 33% decline in women) across the period examined. A decrease in mortality was reported across nearly all the specific types of cancer examined (23 in total), with only liver, oral, and uterine cancers showing an increase together with melanoma skin cancer in men and pancreatic cancer in women, both showing small increases. By contrast, the incidence trends in this age group showed varying patterns with some sites increasing, some decreasing and some remaining relatively constant. Over all sites, a modest increase was noted in cancer incidence rates of around 0.8% per annum in both sexes, amounting to an increase of 15% in men and 16% in women over the 25 year time frame.

The increase in prostate cancer incidence over this period, especially in the 35-69 years age group considered here, is very likely to be a direct result of the uptake of prostate specific antigen testing, which results in the detection of early stage disease and, to an unknown extent, indolent disease that may otherwise never have been regarded as clinically significant. 24 25 The results do, however, affect people diagnosed and represent a large increase in workload for clinical staff. The fact that the overall mortality trends for men show no difference whether prostate cancer is included or excluded in the analysis indicates that the incidence increase for this cancer has largely been of non-fatal disease. That the specific mortality rates for prostate cancer showed an appreciable rate of decline during this time (–1.8% per annum) also indicates improved clinical treatment of the disease or an increase in the proportion of men diagnosed with a favourable prognosis, or both. 24 26 However, the increase in prostate cancer incidence still results in thousands of men each year dealing with the concerns of a cancer diagnosis and the impact this may have on their lives.

Breast cancer comprehensively dominated incidence and mortality trends in female cancer. Even though the average annual incidence increase of breast cancer over this period (0.9%) was modest in comparison to the prostate cancer increase in men (4.2%), breast cancer incidence rates remained substantially higher than those for any other cancer site in either sex. Inspection of figure 4 shows that breast cancer incidence rates (age standardised) increased at a faster rate until around 2003-05 (from 194.7 in 1993-95 to 229.9 in 2003-05), a slower rate from then until 2013-15 (240.8) but have levelled off in the most recent years analysed (238.0 in 2016-18). These changes in the incidence trend likely reflect a reduced effect of the initial incidence increases brought about by mammography screening in the UK introduced from the late 1980s or a possible effect of a decline in usage of hormone replacement treatment. 27 28 However, the effect of hormone replacement treatment on breast cancer risk is small in comparison to other risk factors, 7 and trends in this treatment has varied over time, such as changes in preferred formulations, doses, and treatment durations, 29 30 31 which may impact breast cancer risk levels. 32 33 As has been reported elsewhere, 34 35 36 mortality for breast cancer has declined substantially despite the incidence increase, which is indicative of improvements in early detection (including through screening 37 ) and improved treatment.

The other two major sites of cancer in men apart from prostate cancer, namely lung and bowel cancers, showed substantial reductions in mortality. These results are likely from primary prevention (historical reduction in smoking rates) 38 39 40 41 for lung cancer and earlier detection (including screening) and improved treatment for bowel cancer. 42 43 44 While lung cancer incidence substantially decreased, the incidence rates of bowel cancer remained unchanged. However, closer inspection of the bowel cancer incidence trends over the full period shows an increase from the point the bowel screening programme was first introduced from 2006 in the UK. This rate, however, has now decreased back to the observed level prior to the introduction of the screening programme. As others have shown, the introduction of bowel screening leads to an initial short-term increase in cancer incidence due to detection of as-yet undiagnosed cancer cases, followed by a decrease because of removal of adenomas. 42 45 46 Therefore, bowel cancer incidence trends can reasonably be assumed to decrease further over the coming years, unless other preventable risk factors for bowel cancer affect the trend.

Similarly, lung and bowel were the other two major cancer sites for women (alongside breast cancer), and both showed reductions in mortality. The decline in lung cancer mortality was, however, not as extensive as that for men (–0.5% compared with –3.1% per annum) likely reflecting the different demographic pattern in smoking rates that led to peak smoking prevalence in women occurring around 30 years later than men, albeit at around half the peak prevalence observed in men. 40 47 Smoking prevalence in women has always been lower than in men. 39 48 The lung cancer incidence trends showed a significant increase in women of 0.8% per annum as opposed to the –2.1% per annum decrease in men. That the incidence rate in 2016-18 was still higher in men than in women again is almost certainly a reflection of historical differences in smoking patterns. 39 49 50 Bowel cancer incidence in women followed a similar pattern to men and is equally reflective of the introduction of the bowel screening programme. Bowel cancer mortality in women has declined at a similar rate to men (–2.2% compared with –2.5% per annum), indicative of the same improvements in early detection and improved treatment.

These reductions in mortality across the most common cancers in both sexes are likely a representation of considerable success in cancer prevention, diagnosis, and treatment. Further improvements are likely to be realised from the continued reduction in smoking prevalence, of which smoking prevention policies continue to contribute, 51 alongside the recent move to faecal immunochemical testing in the bowel screening programme adopted throughout the UK during 2019. 52 The recommended rollout of targeted lung screening is expected to further help with the earlier diagnosis of lung cancer where surgery is a viable treatment option and outcomes are vastly improved. 53 54

Although four major sites influenced the overall pattern of cancer incidence and mortality, increases in rates among some of the less common sites do raise concerns. Four cancers showed substantial increases in incidence (more than 2% per annum) in both sexes: liver, melanoma skin, oral, and kidney cancers. All have strong associations with established risk factors: alcohol consumption, smoking, and HPV for oral cancer; 7 55 56 overweight and obesity, smoking, alcohol, and hepatitis B and C for liver cancer; 7 57 58 ultraviolet light for melanoma; 59 60 and obesity and smoking for kidney cancer. 61 62 63 Increases in liver cancer incidence and mortality for both men and women are very concerning, with nearly one in two attributable to modifiable risk factors. 7 With high prevalence of overweight and obesity and diabetes in the general population, other studies expect the rates to remain high. 64 For oral and kidney cancer, despite the association with smoking, incidence rates have not followed the decrease seen for lung cancer incidence in men. This is likely to be due to the smaller proportion of cases attributable to smoking in these two sites. Whilst smoking accounts for around 17% of oral cancers, over one in three are attributed to alcohol consumption. 7 For kidney cancer, smoking is attributable to 13% of cases whereas obesity causes around 25%, however, increasing trends in kidney mortality are shown for this age group and period. 7 Therefore, the increasing incidence trends could potentially have been worse, especially in men, if the reduction in smoking prevalence had not occurred. The increased incidence of melanoma skin cancer is likely to be caused by the increased sunlight and ultraviolet exposure caused by the availability of cheaper air travel to countries with a warmer climate and insufficient regulation of tanning beds until 2010. 65 66

In women, uterine cancer incidence increased by 1.9% per annum; although, this increase was predominantly seen over the period 1993-2007 and since then incidence trends have increased at a slower rate. One of the main risk factors for uterine cancer is the use of oestrogen-based hormone replacement therapy, 67 68 and since around 2000, use has substantially declined. 27 Around a third of uterine cancers in the UK are also attributed to overweight and obesity, but the increase in incidence is also likely to be caused by a decrease in the number of women undergoing hysterectomies for menorrhagia, in favour of endometrial ablation. 69

Other cancers that showed increases in incidence were cancers of the pancreas, brain, and central nervous system, together with Hodgkin and non-Hodgkin lymphoma, myeloma, and leukaemia in both sexes, and oesophageal and testicular cancers in men. With the exception of pancreatic cancer, which only decreased in women, all these cancers also showed a reduction in mortality in both sexes, indicating improving treatment or earlier detection, or both. Generally, the causes of these cancers are not well understood although obesity is associated with the adenocarcinoma histological subtype of oesophageal cancer, 70 especially in men, 7 while a combination of smoking and alcohol is implicated in the squamous cell carcinoma subtype. 71 The considerable male excess in oesophageal adenocarcinoma in comparison with squamous cell carcinoma rates, 72 possibly underlined by the higher incidence of gastroesophageal reflux disease in men 73 and the protective effect of oestrogen, 74 75 may explain the differing trends now observed between men and women.

Several cancer sites showed decreases in both incidence and mortality rates over the time period, notably stomach, larynx, and bladder cancer in both sexes, as well as cervical and ovarian cancers in women and mesothelioma in men. The changes in stomach cancer rates were of a similar magnitude and represented the largest percentage mortality decline in both sexes. This decline can probably be attributed to a combination of a reduction in the prevalence of Helicobacter pylori infection and an increase over time in fruit and vegetable consumption reducing the dependency on preserved foods. 76 77 Challenges in coding of stomach and oesophageal cancer before 2000 may also have had a role in shaping these trends. Laryngeal cancer is associated with tobacco use and alcohol consumption as well as occupational exposures, 56 78 79 and the decline in rates is most likely to be related to the decrease in smoking prevalence as well as decreases in occupational exposure. 80 The refinement of understanding pathology for bladder cancer during this period, in which previously diagnosed malignant disease is now categorised as benign, 81 is likely to have resulted in an artificial decline in incidence rates. 82 83 This artefact should not, however, have affected the decline in mortality rates given the benign nature of these tumours that do not cause death. 81 This decline in mortality, although not as marked as that for incidence, remained appreciable. The changes in cervical cancer rates, which showed the largest percentage mortality decline amongst gynaecological cancers, are almost certainly attributed to the success of the cytological screening programme during the whole of the time period considered. 84 85 With the introduction of the HPV vaccination programme for girls in 2008 86 and the subsequent expansion to boys in 2019, 87 rates of cervical cancer are expected to fall substantially over the following decades as the first cohort of vaccinated women reaches the peak age for cervical cancer incidence (aged 30-34 years). A reduction has already been shown for women aged 20-24. 88 The absolute incidence rates of mesothelioma in women were small in magnitude in 1993-95 (0.8 per 100 000 per annum) and remained similar over time (0.7 per 100 000 per annum in 2016-18). The incidence rates of mesothelioma in men were considerably greater, especially in 1993-95 (around 6.3 per 100 000 per annum), due largely to occupational asbestos exposure, 89 but a significant decrease was noted over time (to 3.6 per 100 000 per annum in 2016-18) resulting from both the decline in asbestos exposure and the decline in heavy industries, such as coal mining. Mortality decreased substantially in both sexes over the period for which data are available (2001-03 to 2016-18).

The conclusions that can be drawn from this analysis are, overall, positive and reassuring. Within the 35-69 year age group, cancer mortality rates have shown a substantial overall decline during the last quarter of a century in both men and women. The most probable causes are a combination of changes in the underlying risk of disease for some cancers (notably lung and stomach), in increased levels of early detection (notably breast 37 and cervix 90 ) and improved treatment (notably breast and bowel) for others. The specific circumstances leading to the increased incidence of breast cancer, of which risk factors are complex, need to be better understood and controlled. Similar results have been shown for incidence within Great Britain and mortality in the UK for some cancer sites. 91 Speculated overdiagnosis, where tumours are detected that would not have caused the patient any harm during their lifetimes, has been thought to increase rates for breast and prostate cancers in particular, of which prostate is especially affected by the widespread use of prostate specific antigen testing. 4 92 However, given the decreases in mortality across the wide set of cancer sites analysed here, improvements in early diagnosis, treatment, or both are having a positive effect for most cancer patients, although cancer mortality in this age group still needs reducing.

After accounting for the major two sites in men and women, the increase in overall incidence rates disappeared in men while it remained significant in women. This difference between sexes is due to a decrease in cancers with substantially higher initial incidence rates in men, such as lung, stomach, and bladder, resulting in a higher overall impact on male incidence, combined with an increase in incidence in uterine cancer, one of the most common cancers in women.

Strengths and limitations

This study benefits from high quality cancer registry data collected by all four cancer registries in each country across the UK, which allows for the inspection of a wide range of cancer sites over 25 years. ICD-10 coding changes have been minimal, only affecting trends in cancer incidence for bladder and ovarian cancers and cancer mortality for mesothelioma, whereas challenges in coding stomach and oesophageal cancer may have affected trends for these sites. Changes in registration practice may well have had a small effect on certain cancer sites. By focusing only on the 35-69 age range, we present a clear and reliable comparative picture of cancer incidence across 25 years within the UK, which provides a reliable indicator regarding future cancer incidence trends. Understanding cancer in older people and changes in the trends of different cancers is also of interest, but subject to a different study given the increasing life expectancy over this period, impact of comorbidities, and differing interaction with health services in this age group.

Limitations include the absence of staging data to substantiate any improvements in earlier diagnosis. Due to the number of sites analysed, we also have not broken down sites by histological type, which could be beneficial in certain sites to understand the trends within cancer sites—eg, small cell and non-small cell lung cancer or oestrogen receptor-positive and oestrogen receptor-negative breast cancer. In focusing on the age group selected, we are excluding older ages where rates of cancer are higher. Although this exclusion reduces the number of cases included, providing a smaller cohort for each year, the age group selected provides a more reliable comparator for future trends given the accuracy of incidence recording and also focuses on the cancers that lead to a larger number of years of life lost. The age range included in this study has been well defined; however, other studies are indicating potentially different trends worldwide in young adults with potential increases in risk factors such as dietary risk factors playing a role. 93 94 The data captured across the UK registries provides a basis for further understanding to see whether different trends are observed across younger age groups and whether the causes of this can be determined. Additionally, although we have included a broad range of cancer sites, cancers that have not been included in this study could well be showing different trends, such as a more recent increase in thyroid cancer in the UK. 95

This study also provides a baseline covering a 25 year period uninterrupted by covid-19. Trends in cancer incidence and mortality beyond these years will be affected and therefore understanding the causes of trends will be more complicated. Having a 25 year baseline provides the observed trend for which expected cases can be assessed against observed. This benchmark will present a comparison for the following decade as the presentation, diagnosis, and treatment of cancer have been hugely affected by rules and regulations affecting public and health service staff. Mortality trends will also be impacted with decision making regarding coding of deaths with covid-19 likely to be the underlying cause of death for people with cancer if that has directly led to the patient dying, rather than their cancer.

This study focuses on the overall sex specific trends for cancer incidence and mortality in the specified age group to observe and understand trends over the 25 year period across the entire UK. Further breakdowns have not been possible. Paucity of numbers for less common cancers precluded separate analyses for the individual UK nations while data limitations precluded analyses by other demographic characteristics, for example, ethnic group and deprivation. The main obstacle to analysing data by ethnic group is the completeness of recordings in hospitals. In England, completeness improved substantially in 2012, but prior to this, the proportion of cases with unknown ethnic group renders results over time to be incomparable. In other UK countries, completeness of ethnic group recording is still not good enough to conduct country-wide cancer incidence or mortality analyses by ethnicity. For deprivation, the measures currently available are derived within each UK nation, and a specific validated UK-wide deprivation measure does not yet exist. Given the obvious importance of looking at variation in UK trends within ethnic groups and deprivation categories, such analyses represent a priority for further research and highlights the importance of data collection across all UK nations.

Conclusions

Overall, these results substantiate the view that in this age group there is no generalised increase in cancer incidence, while there is a substantial decrease in cancer mortality in the UK over the 25 year study period. Specific concerns about individual cancer sites identified were raised, of which the most important numerically, apart from the increases in breast and prostate cancer incidence, was the need to accelerate the decrease in female lung cancer. After which, concerns about oral cancer, liver cancer, kidney cancer, uterine cancer, and melanoma skin cancer present the most pressing issues. There are also several cancer sites that showed decreases in both incidence and mortality, notably, stomach, larynx, bladder, and cervical.

What is already known on this topic

No recent studies have investigated cancer incidence and mortality rates over such a long time frame within the 35-69 year age group in the UK

Short term trends for specific cancer sites are related to known risk factors, screening programmes, and improved treatment

Trends in the 35-69 years age group can be indicative of future patterns of cancer in older people

What this study adds

Decreased rates of many cancers, including lung and laryngeal, is positive, and likely to be driven by the decrease in smoking prevalence across the UK

An increase in rates of other cancer sites, including uterine and kidney, was noted, which may be a result of the increasing prevalence of overweight/obesity and other risk factors

Organised population screening programmes have led to an increase in cancer incidence but also look to have contributed to a reduction in cancer mortality across the UK

Ethics statements

Ethical approval.

Ethics approval for this work was not required as the study used publicly available data.

Data availability statement

Data sharing may be possible for additional analyses. All code used for analyses in this paper are also available from the Cancer Research UK website and GitHub. Information on how to access the data used in this analysis are available from the Cancer Research UK website.

Acknowledgments

This work uses data that has been provided by patients and collected by the health services as part of their care and support. The data is collated, maintained, and quality assured by NHS England, Public Health Wales, Public Health Scotland, and the Northern Ireland Cancer Registry.

Contributors: All authors participated in study conception and design, and/or the analysis and interpretation of results. Conception and design: DF, LS, and CT. Analysis and interpretation: all authors. Writing manuscript: all authors. Supervision and guarantor: JS and DF. All authors critically reviewed drafts of the manuscript, read and approved the final manuscript. The corresponding author attests that all listed authors meet authorship criteria and that no others meeting the criteria have been omitted.

Funding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ declare: no support from any organisation for the submitted work; no financial relationships with any organisations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work.

The manuscript’s guarantor (DF) affirms that this manuscript is an honest, accurate, and transparent account of the study being reported, that no important aspects of the study have been omitted and that any discrepancies from the study as planned have been explained.

Dissemination to participants and related and public communities: study results will be disseminated to the public and health professionals by a press release written using layman’s terms; findings will also be shared through mass media communications and social media postings. A webinar produced alongside a patient advocacy group is also planned to accompany the publication of this study, a recording of which will be made available on the Cancer Research UK website. Since the study analyses cancer registry data collected during routine care, and provided in aggregated form, we are unable to specifically disseminate results to study participants beyond the usual channels of publication.

Provenance and peer review: Not commissioned; externally peer reviewed.

This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/ .

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Causes of cancer and reducing your risk

Can cancer be prevented?

Around 4 in 10 UK cancer cases could be prevented.

What's my cancer risk?

Find out how to reduce your risk of cancer.

Smoking and tobacco

If you smoke, stopping is the best thing you can do for your health and to reduce your cancer risk.

Obesity and weight

Keeping a healthy weight reduces the risk of 13 different types of cancer.

Staying safe in the sun and avoiding sunbeds reduces the risk of melanoma skin cancer.

Diet and healthy eating

Eating a healthy balanced diet can help reduce your risk of cancer.

The less alcohol you drink, the lower your risk of cancer.

Physical activity

Being more active can help us keep a healthy weight and reduce the risk of cancer.

HPV and infections

You can’t catch cancer, but some infections such as HPV can increase your risk.

Changes in our hormone levels can affect the risk of cancer.

Air pollution and radon gas

Air pollution and radon gas increase the risk of lung cancer, but in the UK the risk is relatively small. 

Cancer myths

Hoaxes, myths and unanswered questions about cancer.

Inherited cancer genes

Some inherited faulty genes can increase your risk of cancer.

Workplace cancer risks

Some jobs can affect people’s risk of cancer.

Age and cancer

Cancer is more common as we age.

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What to Know About Rising Rates of 'Early-Onset' Cancer

BY KATHY KATELLA March 4, 2024

Many people think of the first few decades of adulthood as a time of exploration—to focus on a career, make new friends (or even find a spouse), travel the world, or just have fun. Whichever path they choose, the last thing on their mind is cancer. But cancer is occurring in more adults at younger ages—before they turn 40 or 50 and sometimes even earlier.

These are called “early-onset” cancers, which are diagnosed in adults between the ages of 18 and 49. Because advancing age is the top risk factor for cancer in general, the recent rise in early-onset cancers is worrisome.

Many individuals in this age group are too young for recommended routine cancer screenings—for example, mammography screening typically starts at age 40 and colonoscopies at age 45. And busy lives make it difficult to keep up with routine primary care visits, where family history might prompt a doctor to suggest an earlier screening. Others may not go to the doctor because they have limited or no health insurance—or they believe their health problems are not serious enough to warrant a visit. This can result in diagnosis delays, which raise the risk of cancer potentially being diagnosed at a more advanced stage, which may be harder to treat.

Why are younger people getting cancer? “It's such an important question, and it points to the need for more research in all kinds of domains—in population science, behavioral health, public health, and basic science as well,” says Veda Giri, MD , a Yale Medicine medical oncologist and director of Yale Cancer Center’s Early-Onset Cancer Program at Smilow Cancer Hospital , which brings together such components as research, clinical services, and care from psycho-oncologic specialists, including psychiatrists and social workers.

“So, right now, we are focusing on recognizing that early-onset cancer is a different type of cancer and providing more support for these younger patients,” Dr. Giri says.

Below, Yale Medicine specialists who care for patients with early-onset cancer answer questions about the uptick in diagnoses and the importance of family history.

How are early-onset cancers different from other types of cancer?

Age itself is the first and obvious difference. “Early-onset” can be defined in various ways based on the cancer type. “For example, early-onset breast cancer refers to a diagnosis in someone younger than age 45, while early-onset colorectal cancer is a diagnosis that occurs in someone younger than 50,” says Dr. Giri. “To be as inclusive as possible, the Early-Onset Cancer Program at Yale is addressing the needs of patients diagnosed with cancer between the ages of 18 and 49.”

At age 50, cell damage begins to build up in the body, and the rate of cancer incidence climbs steeply through the following decades. A cancer diagnosis before age 50 is not uncommon, but it’s also not the trajectory most people expect, considering the median age for a cancer diagnosis is 66 years old.

Another difference is that certain cancers, such as breast cancer, tend to be more aggressive in younger adults, says Yale Medicine’s Mariya Rozenblit, MD , a medical oncologist.

“While older women are more likely to be diagnosed with slow-growing, estrogen-positive tumors, younger women have more triple-negative and human epidermal growth factor receptor 2 [HER2] breast cancers, which are more aggressive types,” Dr. Rozenblit says. The latter cancers often require more aggressive treatments, especially if the cancer is already spreading in the body, and those treatments can have significant side effects, she adds.

“Younger women diagnosed with breast cancer are also more likely to have a genetic mutation than older women,” says Dr. Rozenblit. But she cautions that while genetics are getting more attention, mutations like BRCA only account for about 20% of early-onset breast cancers. “So, there are clearly other contributing factors that we don’t yet know,” she says. “The good news is that once breast cancer is diagnosed, the prognosis is usually very good. The treatments can be long, but we still have very high cure rates, and these younger women often end up doing extremely well.”

Jeremy Kortmansky, MD , a Yale Medicine medical oncologist specializing in gastrointestinal cancers , also sees differences when younger adults are diagnosed with colorectal cancer. “Some of the molecular characteristics and pathways of how something becomes cancerous are different between the older and younger groups,” he says. “Younger adults tend to have a more aggressive-appearing cancer. They also tend to present at a more advanced stage that is not solely explained by a delay in diagnosis.”

Some of this may be explained by the fact that they are too young for routine screening, but there's probably more to the story. We just don’t have answers yet, he adds.

What types of cancers are on the rise in younger adults?

While some cancers have been declining in older people, various reports and studies have shown that cancer is on the rise in younger adults. One of the most recent is Cancer Statistics, 2024 , an American Cancer Society (ACS) annual report on cancer facts and trends. Published in January, the report revealed that while cancer deaths are falling, new cases are ticking upwards—from 1.9 million in 2022 to over 2 million in 2023.

More of those new cases involve younger people. The ACS report showed younger adults to be the only age group with an increase in overall cancer incidence between 1995 and 2020—the rate has risen by 1% to 2% each year during that time period.

The ACS report also showed continued increases in such common cancers as breast, prostate , and endometrial in young adults, as well as colorectal and cervical cancers. Colorectal cancer, while still overwhelmingly a disease that affects older people, is now the leading cause of cancer death in men younger than 50 and second in women in that age group. The numbers have been rising steadily in people 55 and younger since the mid-1990s, according to the ACS.

As for cervical cancer, the ACS report had both good and bad news. Rates of cervical cancer dropped significantly in women in their 20s, who were among the first to get the human papillomavirus (HPV) vaccine , which can prevent more than 90% of HPV-attributable cancers . But for women ages 30 to 44, rates rose 1.7% each year from 2012 through 2019. The increase highlights the need for more screening in younger women and a broader uptake for the vaccine, according to the ACS report.

How can family history help adults who are too young for routine screenings?

Because doctors and researchers don’t yet know why early-onset cancers are increasing, they are focusing on efforts to diagnose these cancers early, when they are typically more treatable. And family history has emerged as a key factor in early diagnosis.

This is partly because young adults don’t always meet the recommended age for routine screenings that are available for some of these cancers. For instance, because colonoscopy screening typically starts at age 45, most cases in adults younger than 45 are not identified until they start noticing signs and symptoms.

But talking to a doctor about a family history of colorectal cancer could prompt a screening referral at a younger age. “If there is a family history of either cancer or polyps, we usually start colonoscopy screening 10 to 15 years before the family member who had it was diagnosed,” says Dr. Kortmansky. “So, if a first-degree relative was diagnosed with cancer at 45, you would start screening at 30.”

Likewise, women who are at average risk for breast cancer may start mammography screening at age 40, according to U.S. Preventive Services Task Force (USPTF) recommendations updated in 2023 . But women with a family history of breast cancer are generally advised to start when they are 10 years younger than the first-degree relative (a mother and/or sister) was at their time of diagnosis.

“We’re beginning to recognize that family history is very important,” says Dr. Rozenblit. “For young women who have a significant family history of cancer in the family, we are starting to refer them to a high-risk clinic —even if the cancer in their family is not breast cancer.”

Depending on family history, calculators can be used to further estimate a patient's cancer risk, and advanced screening like MRIs or other diagnostic procedures may be offered, adds Dr. Giri.

“Family history can inform genetic testing to find out whether a person has a mutation that makes them predisposed to developing a certain type of cancer,” she says. “But even if patients test negative for genetic mutations, family history may be a reason to follow them more closely.”

How can early-onset cancer affect a younger adult’s life?

Nancy Borstelmann, PhD, MPH, LCSW , co-director of Yale’s Early-Onset Cancer Program, says that while a cancer diagnosis and treatment are challenging for most people, there are some heightened and unique concerns for someone in their 20s, 30s, or 40s.

One key example is family planning, since some cancers and treatments can create challenges with being able to become pregnant or produce sperm. “It depends on each person’s situation—for example, their age, type of cancer, and treatment plan. But patients may face a decision about freezing eggs or embryos , or whether to consider sperm banking,” Borstelmann says. “Reproductive concerns can add to the distress that cancer patients are already experiencing, and they are important issues for patients and their doctors to discuss. Additional challenges include worries about insurance coverage and the financial impact of taking steps related to family planning .”

Younger women may also be concerned that cancer treatment could pose a risk of early menopause. Chemotherapy may induce menopause, or, in some cases, hormonal treatments are part of a treatment plan specifically designed to produce an early menopause. Whatever the cause, Borstelmann notes, early menopause shortens a person’s fertility window and can have other effects on their overall physical and emotional well-being.

Body image is yet another concern. There are many aspects to body image, but, for some, a clearly visible issue to manage is hair loss, which can be a side effect of chemotherapy, Borstelmann says. “For some, it's very distressing.”

Sexual function and sexual health issues are also common and can range from changes in bodily sensation (for example, for a woman who has had a mastectomy) to erectile dysfunction (for example, after prostate cancer treatment). Younger individuals diagnosed with any type of cancer, however, may struggle with the direct or indirect impact of cancer on their sexual health and how they feel about their bodies. Some describe a sense of loss and fear related to developing or sustaining intimate relationships.

What’s more, because cancer is happening at such young ages, even after treatment, there is the possibility that the cancer could come back, which is especially difficult for survivors who still have decades of life ahead of them. This is a particular concern for those with thyroid cancer , who face a risk of recurrence that is highest in the first five years after diagnosis and treatment, but persists throughout their lifetime, says Yale Medicine endocrine surgeon Courtney Gibson, MD, MS . “Since the life expectancy of young adults remains largely unchanged after a thyroid cancer diagnosis, the fact that recurrence can happen at any time is very unsettling,” she says. “However, we can provide reassurance that if it returns, we still have effective ways to treat it.”

Is there any way to avoid early-onset cancer?

The advice on the topic—for everyone—remains the same: Pay attention to exercise and nutrition, don’t smoke or drink too much alcohol, and be aware of family history and share it with a primary care physician, the doctors say.

Following up with a doctor and fully checking out any unusual symptoms can be critical, Dr. Kortmansky adds. “There is often a delay between the onset of symptoms and the actual diagnostic procedure to find the cancer,” he says. “Some of that may be driven by patients who think, ‘I'm only 40—it's probably not cancer, right?’ Other times, a physician may think rectal bleeding in a young patient is just a sign of hemorrhoids, so it’s important to advocate for yourself.”

At the same time, no patient should feel guilty or ashamed if they are diagnosed with cancer, Dr. Giri and Borstelmann say, describing two common reactions they say some of their young patients have. “It can be a human response to ask, ‘Did I do something wrong?’” Dr. Giri says. “I've seen this in some incredibly health-conscious patients who ate well and exercised. They feel completely thrown by this and need to know it’s not their fault.”

Each patient is different, and a key component of the Early-Onset Cancer Program at Yale is to ensure that patients have a place where they can talk about their feelings and experiences, Dr. Giri says. “Young people need to feel supported and holistically cared for through the course of their cancer and beyond,” she says.

More news from Yale Medicine

Too young to screen: breast cancer in younger women.

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Why Are So Many Young People Getting Cancer? It’s Complicated

J ust this month, two young, high-profile public figures announced that they have cancer. First, Olivia Munn, 43, disclosed that she was treated for breast cancer after catching it early. Days later, Kate Middleton, 42, announced she has been receiving treatment for an unspecified form of cancer .

Their diagnoses spotlight a troubling trend: both in the U.S. and around the world, cancer diagnoses are growing more common among adults younger than 50. By 2030, one recent study estimated , the number of these early-onset cancer diagnoses could increase by roughly 30% worldwide—and the number of people who die from their conditions could rise by about 20%.

“The most striking finding in the last decade has been this rise in incidence rates among young adults,” says Ahmedin Jemal, senior vice president of surveillance and health equity science at the American Cancer Society (ACS).

Cancer is still most commonly diagnosed among people older than 65 . In the U.S., only about 12% of cancers are diagnosed among adults younger than 50, according to ACS data . A woman in the U.S. has about a one in 17 chance of being diagnosed before she turns 50, while a man has about a one in 29 chance, the ACS says. (Women are more likely to be diagnosed largely because breast cancer is so common.)

Read More : The Race to Make a Vaccine for Breast Cancer

But those odds are gradually getting worse. In 2019, about 103 cancers were diagnosed among every 100,000 U.S. adults younger than 50, up from about 100 in 2010, according to a 2023 study in JAMA Network Open . That may seem like a small overall increase, but it’s not a good sign—especially since, during the same period of time, incidence rates among older U.S. adults decreased. “It’s almost like the curves have reversed themselves,” says Dr. Richard Barakat, director of cancer care at Northwell Health in New York.

For certain types of cancer, the numbers are especially striking. Colorectal cancer is now diagnosed among young adults almost twice as often as it was in the 1990s, according to one 2022 study , and the JAMA Network Open researchers found that other types of gastrointestinal cancer are also on the rise among this population. Early-onset breast cancer is becoming more common too, with its incidence rising by almost 4% among U.S. women every year from 2016 to 2019, according to a 2024 study . Even lung cancer, a disease typically associated with older cigarette smokers, is now to a surprising degree affecting younger women , even those who have never smoked, says Dr. Matthew Triplette, a pulmonologist at Fred Hutch Cancer Center in Seattle.

What’s driving these trends? Triplette says he doubts there’s “some new, very dangerous cancer risk factor out there that’s causing tons of excessive cases in younger folks.” Cancer is a complex disease influenced by a mixture of genetics, lifestyle choices, and environmental exposures, so it’s unlikely that there’s a single explanation for the data.

Instead, it’s likely a mix of things. Eating lots of processed foods , not getting enough exercise , and drinking too much alcohol are all risk factors for cancer, and all of those issues are widespread in modern life. A 2019 study co-authored by Jemal found that many of the cancers growing more common among U.S. young adults are linked to obesity, which now affects about 40% of U.S. adults under 40 .

Read More : Microplastics in Bottled Water at Least 10 Times Worse Than Once Thought

Researchers are also studying the gut microbiome’s role in cancer development . Everything from what you eat to the medications you take can affect the health of your gut microbiome, Barakat says, so it’s feasible that aspects of the modern diet—or the medical system’s over-reliance on antibiotics —could have trickle-down effects. Exposure to pollutants in the environment could play a role, too, Triplette says.

Even big societal changes could have an impact, Jemal says. For example, research shows that women who give birth to their first child at 35 or younger tend to have a lower risk of breast cancer. In many countries, increasing numbers of women are now choosing to have children later in life or not at all, which could be reflected in cancer rates, Jemal says.

To help lower the risk of cancer, everyone can benefit from evidence-backed health advice like eating a balanced diet, getting plenty of exercise, and not smoking or drinking heavily. But, ultimately, each individual’s chance of getting cancer is different. People with specific risk factors—like genetic markers or a family history of cancer—should consult a doctor about early screening and other preventive measures, Barakat says. Getting a head start can be crucial, he adds, because people with genetic predispositions to cancer are often diagnosed fairly early in life.

It’s also important, Barakat says, to know your body and see a doctor if you think something is wrong. “When I look at some of the patients who were diagnosed with early-onset colorectal cancer, they had symptoms, but nobody thought that a 30-year-old had colon cancer,” he says. The longer it takes to detect cancer, the harder it may be to treat—so it’s important not to assume everything is fine just because you’re young and seemingly healthy.

Of course, every episode of gastrointestinal distress or bloating isn’t a sign of something serious; often, these issues are nothing more than uncomfortable. But if you're having unusual symptoms that “continue for a long time, you definitely have to look into it,” Barakat says. "And doctors have to be more aware and be a little bit more suspicious.”

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New report sparks questions and controversy over possible causes of Iowa ‘cancer crisis’

Binge drinking not seen as cause of Iowa’s rising cancer rates, researchers say.

Amid increasing scrutiny of a potential link between agricultural chemicals and cancer, a new report is generating controversy as it blames rising rates not on the toxins used widely throughout the state, but on something else entirely: binge alcohol consumption.

The Iowa Cancer Registry, a health research group housed at the University of Iowa, reported on Feb. 20 that Iowa has the second-highest and fastest-rising incidence of cancer among all states. An estimated 21,000 new cancer cases are expected to develop this year and 6,100 Iowans will die from cancer, said Mary Charlton, Iowa Cancer Registry director, in announcing the report. Iowa, she said, has the highest rate of binge drinking in the Midwest with 22% of residents reporting binge drinking, more than the national average of 17%. Overall, Iowa has the fourth-highest incidence of alcohol-related cancers in the U.S., according to the report.

“Alcohol is a known carcinogen and a risk factor for several cancers including oral cavity, pharynx, larynx, esophagus, rectum, liver, and female breast cancers,” Charlton said in a news conference.

The assessment has drawn questions and sparked doubts, however, from state leaders and health and environment researchers who have been calling for a probe into how much the state’s agricultural industry may be contributing to the spread of disease.

“Is alcohol responsible for the increase in cancer incidence here since 2014? I personally doubt that,” said James Merchant, a retired professor of occupational and environmental health, and former founding dean of the University of Iowa College of Public Health.

“What needs to be looked at are things that are probable or possible carcinogens that have increased beginning about 1990, because of the well-recognized latency of environmental cancers,” said Merchant, who is a nationally-renowned authority on environmental toxins and has led research on the effects of air pollutants on respiratory diseases, including cancer. “Those carcinogens associated with industrial agriculture are the ones that really need to be looked at very closely.”

Charlton did not respond to an interview request for this article.

Pesticides and fertilizers

Iowa is the leading U.S. corn and soybean growing state, with millions of acres devoted to the crops. Corn and soybean farmers typically make heavy use of pesticides and fertilizers on their fields. Iowa farms use more weed killers (35 million pounds) and apply more commercial fertilizer (11.6 billion pounds) every year than any other state, according to federal data . The chemicals are known to contaminate both soil and water and leave pesticide residue in the harvested grains.

Researchers have long suspected that exposure to a number of the most popular pesticides, particularly glyphosate (the active ingredient in the Roundup brand of herbicide), may cause human cancers. In 2015, the International Agency for Research on Cancer classified glyphosate as “probably carcinogenic” to humans. Other studies have found that exposure to other common pesticides are associated with cases of non-Hodgkin lymphoma, leukemia, brain, and prostate cancers.

Iowa’s sprawling livestock and poultry sector is also a concern. The Iowa operations produce more animal manure (54.5 million tons) every year than any other state, according to federal data. For instance, the state’s hog population has grown to 24 million hogs, up more than 70% from 1992. Iowa’s manure production in total has increased almost 80% since 2002, according to the latest U.S. Agriculture Census.

Manure from the animals contributes to the creation of nitrates, which form when nitrogen from fertilizer and manure combine with oxygen. The waste routinely drains from farm fields into groundwater, streams and rivers, contaminating water sources. Babies can suffer severe health problems when consuming nitrates in drinking water, and a growing body of literature indicates potential negative health effects that include an increased risk of cancer . And exposure to elevated levels of nitrates in drinking water from commercial fertilizer and manure has been linked by numerous researchers to cancers of the blood, brain, breast, bladder, and ovaries.

David Cwiertny, professor of civil and environmental engineering and director of the Center for Health Effects of Environmental Contamination at the University of Iowa, recently started working with the Iowa Cancer Registry to explore potential environmental factors contributing to the state’s cancer rates. He noted that multiple risk factors could be contributing to the problem, including nitrate exposure. Research studies show this is especially the case with colorectal cancer — ranked eighth in incidence among all states — and breast cancer, ranked ninth.

“We’re unique in terms of our production system here. Unrivaled anywhere in the world, right?” Cwiertny said. “We’re proud to boast about that. But we shouldn’t be so foolish as to think that the unrivaled scale of production doesn’t come with very unique consequences or challenges for our state, right?”

The new registry findings focusing on alcohol consumption and not agricultural chemicals come as public interest in cancer has swelled across the Corn Belt.

Legislation to invest more state funds in research that identifies environmental sources of cancer has been introduced in Iowa, as well as Nebraska.

In Minnesota, legislators are proposing to introduce a sales tax on commercial fertilizer to pay for closing drinking wells contaminated with nitrates and supplying thousands of southeast Minnesota residents with clean sources of water. The U.S. Environmental Protection ordered Minnesota to halt nitrate contamination in groundwater last November.

Drinking and disease

Alcohol consumption is a known risk factor for certain cancers. Nearly 4% of cancers diagnosed worldwide in 2020 can be attributed to alcohol consumption, according to the World Health Organization. In the United States alone, about 75,000 cancer cases and 19,000 cancer deaths are estimated to be linked to alcohol each year. Alcoholic drinks contain ethanol, a known carcinogen , according to the National Cancer Institute.

And yet, linking alcohol to rising cancer rates in Iowa seems questionable given some of the data points. Iowa’s per capita consumption of alcohol ranks 24th in the nation, according to Statista, a data research service. Nor do drinking habits in Iowa appear to have changed dramatically in the last few decades. Though about a fifth of those who drink alcohol in Iowa identify as binge drinkers — five drinks at a sitting for men, four for women — Iowa’s binge drinkers don’t appear to be drinking more heavily now than years ago. On average, Iowa’s binge drinkers consumed 586 drinks a year in 2017, the latest year for data, which is six more than in 2011. And Iowa was one of the 39 states where binge drinking “did not change significantly during that period,” according to the Centers for Disease Control and Prevention.

"Is alcohol responsible for the increase in cancer incidence here since 2014? I personally doubt that. What needs to be looked at are things that are probable or possible carcinogens that have increased beginning about 1990, because of the well-recognized latency of environmental cancer."

Additionally, Iowa’s increase in cancer incidence appears to have started around 2012, according to the CDC and the Iowa Cancer Registry. That rise in incidence is about 20 years — the scientifically accepted cancer latency period — after the start of Iowa’s rapid industrialization in farming.

“Having a high cancer rate doesn’t immediately translate to its being caused by industrial agriculture. Although I think there is just a strong reason to look very hard in that direction,” said Merchant, the retired professor of occupational and environmental health. “(The cancer registry) wants to be very, very sure of the ground they stand on given the power politics in this state. Everybody understands that. My view is that shouldn’t keep you from asking the question. And those questions need to be asked.”

A ‘cancer crisis’

Public confirmation last year of Iowa’s high cancer incidence also converged with what most adult Iowans already knew in private. Cancer is prevalent in Iowa. Among the 25 counties in the U.S. with the highest incidence of cancer, Iowa’s Palo Alto County ranks second. Roughly 21,000 Iowans now develop cancer in Iowa annually, according to the Iowa Cancer Registry. That’s more than twice as many cancers as occurred in 1973 in a state where the current population — 3.2 million — is a mere 11% higher than it was 50 years ago.

Democrats in the state House and Senate proposed legislation this year to increase funding for health studies aimed at definitively identifying the sources of malignancies.

"We have a serious problem in Iowa. We owe it to Iowans not to whitewash anything — but to approach it scientifically and get to the bottom of this, wherever research and clinical tests lead us."

“We need to make this statement, given the rising cancer rates here and our number two rate in the country,” said State Sen. Janice Weiner, who proposed a bill in January to invest $5.25 million for research on pediatric and other cancers to stem what she called “Iowa’s cancer crisis.”

“I have colleagues on the House side who have filed similar legislation that has bipartisan support,” she said. “So I’m hoping it will move forward. We have a serious problem in Iowa. We owe it to Iowans not to whitewash anything — but to approach it scientifically and get to the bottom of this, wherever research and clinical tests lead us.”

This article was edited by Carey Gillam, managing editor  of The New Lede  and Investigate Midwest.

Keith Schneider is senior editor and chief correspondent with  Circle of Blue .

What causes breast cancer?

T here is a lot going on within the field of breast cancer research. A new AI tool is trying to fine-tune the screening program, another one is helping pathologists make diagnoses. New drugs are approved. This could save more lives. But there is still no answer to the trickiest question of all: What causes breast cancer?

Breast cancer is a well-funded area of research. This is evident from a study published in The Lancet in 2023, in which researchers attempted to determine the actual distribution of a total of 24.5 billion dollars spent on cancer research at global level between 2016 and 2020. The single form of cancer that received the most money was breast cancer: 11.2% of the entire pot.

The abundant funding has had an impact. Mortality from breast cancer has fallen faster than mortality from other cancers. In 1980, 57.5% of patients survived at least 10 years with the disease. By 2022, the corresponding figure was 87.6%.

At the same time, the incidence curve shows an increase at all ages, most notably for women aged between 50 and 70. In 1980, 105 per 100,000 individuals were diagnosed with breast cancer in Sweden. By 2022, this figure had risen to 191 per 100,000. The increase is still ongoing and over the last two decades the number of cases has increased by about 2% per year.

More than 1 in 10 women over the age of 75 have been diagnosed with breast cancer, making it the most common cancer among women. In 2022, more than 8,500 people were diagnosed with breast cancer, including 57 men.

Thus, the disease is common and becoming more common, while survival rates are improving. Early detection, better diagnostics and more effective treatments are behind this success.

In Sweden, screening with mammography was gradually introduced starting in the 1980s. Today, all women between the ages of 40 and 74 are offered a free examination every 18 to 24 months.

Equal for all, in all regions. Very fair?

Absolutely not, says Per Hall, Professor at the Department of Medical Epidemiology and Biostatistics.

"Some women have a low risk of developing breast cancer while others have a very high risk. It is highly individual. We have had this knowledge for many years, but despite this we still screen everyone in the same way," he says.

New model for risk-based screening

Per Hall has spent the last decade developing a model for risk-based screening. With that goal in mind, an AI tool has had to work self-learning with mammography images from healthy women, images where it is known who later developed breast tumors. It may sound like a simple matter to enter a number of images into a system, but Per Hall describes a major challenge in making tens of thousands of images comparable even though they come from different digital environments, where different software has been used.

"It took several years to teach our software to treat all mammography images in the same way, whether the machine that took them was a Siemens or a Philips or any other brand," he says.

AI already has a place in the mammography business, with digital tools assessing the images. This way, radiologists can be relieved. In some mammography units, there is now one radiologist and AI looking at the images, instead of two radiologists as before. In those cases, the AI tool is tasked with answering the question "Are there any suspicious tumors in this breast?"

But the AI that Per Hall has been working on has learned something completely different. It is trained to answer the question "How likely is it that this breast will develop a breast cancer within two years?"

"The tool identifies and assesses a variety of parameters that the human eye cannot see. These include mammographic density in relation to age, calcifications and differences between the right and left breast," explains Per Hall.

Breast density is an important risk factor for breast cancer. Density is not something that can be seen or felt by the woman herself, but can be seen on a mammogram. A small amount of fat but a lot of breast tissue and connective tissue results in a dense breast. Conversely, a lot of fat and little other tissue results in a lower degree of density. In a dense breast with lots of breast tissue, there are more cells that can turn into cancer cells. It is also more difficult to see any tumors, as a dense breast will appear white on a mammogram, hiding any lump, which will also appear white on the image.

Risk factors affect the breast density

The density changes throughout life as breast tissue is converted to fat. In a 25-year-old, an almost completely white mammogram image is expected, but the same image from a 70-year-old woman would be a clear sign of a high risk of disease. Per Hall says that virtually all known risk factors for breast cancer affect density. Each child born and breastfeeding reduces density—so conversely, delayed childbirth, few children born and limited breastfeeding increases density. Alcohol and lack of physical activity increase density, as does post-menopausal obesity, late menopause or hormone therapy to relieve menopausal symptoms. The only known risk factors that reduce density are smoking and age.

"For some reason we don't know, smoking reduces the density while increasing the risk of breast cancer. But smoking is a risk factor—albeit a weak one—in this context," says Per Hall.

But many women have a lifestyle that includes the above-mentioned risk factors, without getting the disease. And some who get the disease are young, have given birth to several children early, drink sparingly and exercise frequently.

So many of the known risk factors for breast cancer are quite weak. But in a large group of women, as in a whole population, they make a difference. When an entire population changes its lifestyle in a certain direction, for example by postponing childbirth and having fewer children, this can partly explain why the disease is becoming more common.

A few known risk factors play a major role at the individual level. These include older age and, somewhat obviously, female gender. But also mutations in the BRCA1 and BRCA2 genes. They are rare, but they greatly increase the risk of developing the disease. Up to 5% of all breast cancer is caused by these mutations.

Per Hall believes that new knowledge about the genetics of breast cancer will eventually shed more light on the risk factors. He believes that certain gene variants, perhaps in combination with certain other gene variants, can amplify the effect of certain risk factors, leading to the development of the disease in an individual. But capturing that kind of combination of multiple factors, which are individually quite weak, in combination with one or more gene variants, requires enormously large studies to provide outcomes.

"We've collaborated with a large number of groups around the world and done studies involving about 400,000 women—but we're still not getting results. So we need even more participants to capture any patterns," says Per Hall.

It all boils down to the fact that it is currently impossible to say why a particular woman has developed breast cancer. Nevertheless, the researchers' goal is to be able to say approximately how likely it is that an individual woman will contract the disease within two years. And then renew the existing screening program from that perspective.

"Yes, exactly, that's what we are aiming for. We will test a possible approach in a study that starts now in April," says Per Hall.

The study he is talking about is called SMART and is part of the larger Karma project, which includes a large number of studies with different questions about breast cancer. In SMART, 70,000 women will be randomized into two groups. Half will be invited to join the existing screening program and offered screening at the current intervals. The rest will be risk assessed by the AI tool developed by Per Hall's research team. They will then be offered individually calculated intervals, where the high-risk women will be examined every year.

The high-risk women will also be examined in a different way, with a contrast agent injected via a vein in the arm before imaging. The agent seeks out any tumors that light up like little stars in the mammogram image, even whiter in all the white. The method is called contrast-enhanced mammography.

The hypothesis is that this will make it possible to find more breast cancers through screening. But—and this is tricky—not all breast cancers are equally important to find, as strange as that sounds.

A recurring criticism that has followed the mammography screening programs since their early days is that the more aggressive tumors slip through more easily. These tumors are more often detected when the woman herself feels a lump and therefore seeks care. Since this happens between the appointments in the screening program, it is called interval cancer.

Today, about two-thirds of breast tumors are detected through the screening program and about one in three breast cancers are interval cancers.

"It is the interval cancer that we want to address. We know that if you add more examinations to the screening program, you will find more tumors. But some of them can be considered as overdiagnosis. The important thing is to find cancers that would otherwise become interval cancers. This is how you manage to catch more cases of aggressive cancer at an earlier stage," says Per Hall.

The AI tool developed by his research team has recently been tested in a study with patients from four other European countries. The aim was to find out whether the tool also works in digital environments where it has not been trained. This resulted in a study recently published in The Lancet Regional Health .

The researchers included more than 8,500 women who all went home with good results from their mammograms. In that group, the researchers had "hidden" 739 women who were diagnosed with breast cancer within two years, before they attended their next screening appointment.

The question was: Does the AI tool find them? The answer is: Some.

In the large group of just over 8,500 women, the tool has deemed just over 529 to be at "high risk" of getting an interval cancer. And in this smaller group, nearly one in three women did indeed get it. And of those, about one in three had disease that had grown slightly larger or spread to lymph nodes in the armpit.

"The tool succeeded in detecting both interval cancer and more aggressive cancer. And with a method that is not particularly expensive—we don't do any genetic analysis or MRI scans," says Per Hall.

In the best case, a trimmed screening program can contribute to more tumors being found early. But once they are caught, accurate diagnosis is crucial for the patient to get the best possible treatment. And AI has an important role to play here too.

"AI is at its best when it comes to seeing patterns in images. The use of AI in pathology will be of great importance and is a journey that has only just begun," says Johan Hartman, Professor of Tumor Pathology at the Department of Oncology-Pathology at Karolinska Institutet.

He describes a rapid pace of development, with digitalization still ongoing. Many hospitals have put away the microscopes and are fully digital. In other places, the transition is still ongoing. In parallel, the next stage of development is already taking place, supported by AI.

More specifically, digital pathology means that a tissue sample is first handled manually, just like before. For example, a specimen may be thinly sliced and placed on a glass slide. It is then sent into a scanner that can photograph hundreds of slides at a time.

It is these extreme close-ups of the tumors that pathologists analyze. In many cases, this involves counting, assessing and evaluating. For example, a certain percentage of cells must have receptors for estrogen and progesterone for a tumor to be considered hormone sensitive. The proportion of cells in the division phase describes the growth rate. There are other aspects that are important for categorizing a tumor.

"But we are only human. It is difficult to quantify different things in an image," says Johan Hartman.

At least for a human. An AI can count every cell in an image and assess it—at lightning speed.

"These systems, where AI helps us count, already exist today. I think they will soon become a requirement in pathology," he says.

A number of parameters

Johan Hartmans research focuses on the next generation of AI—a more analytical model, capable of assessing the severity of disease in the cells on the screen.

"That's the type of AI I'm most interested in. These are systems that will have a major impact on diagnostics," says Johan Hartman.

He and his colleagues have developed an AI tool that is already being used to assess hormone-sensitive breast cancer, which accounts for about 80 of cases. This large group is divided into lots of different subgroups, in different ways.

The concept of tumor grade is relevant in this context. This assessment is based on a number of parameters. For example, in addition to growth rate, the pathologist must estimate how abnormal the cells are, in general—what do the cell nuclei look like, how much do they differ from healthy cell nuclei? And are the cancer cells similar or different from each other?

"A human is capable of holding a maximum of ten variables in his or her head and weighing them together in an overall analysis. This AI system is capable of assessing and weighing thousands of variables," says Johan Hartman.

Today, breast tumors are divided into three groups, where tumor grade 1 means a low risk of recurrence and spread, while tumor grade 3 is associated with higher risks.

But in practice, more than half of the tumors fall into an intermediate group, grade 2. This means thousands of cases per year. And for them, the choice of treatment is less obvious.

"Oncologists often choose the safe option and add chemotherapy and radiation in many cases. This means that there are patients in this intermediate group who are overtreated," says Johan Hartman.

The AI he has developed has accessed thousands of images representing grade 1 and 3 tumors. The tool has had to work self-learning in this large image material and train itself in pattern recognition. The goal was to figure out what separates the two groups.

And the system has succeeded in doing so. When the tool assesses images from the large intermediate group, it manages to place the tumors along a scale, with some closer to grade 1 and others closer to grade 3. In studies where the researchers have known which patients who have later relapsed, it has been shown that the tool makes good assessments.

Some hospitals in the country have already started using the AI tool to support them.

"The tool contributes to a more uniform assessment of the tumor. We know today that assessments can vary depending on the pathologist who makes them. This is a problem because it can affect treatment choices. This tool contributes to a common understanding of tumor categorization, regardless of where in the country the patient is treated," says Johan Hartman.

Over the last decade, a number of new drugs have been developed in the field of breast cancer, such as CDK4/6 inhibitors, which can slow down hormone-sensitive disease that has spread beyond the breast and armpit. There have also been several new immune therapies that help the body's own immune system fight the tumors. There are more new treatments in addition to these, including several that improve the effectiveness of the anti-hormonal treatments used for hormone-sensitive cancer.

Theodoros Foukakis, an oncologist and research group leader at the Department of Oncology-Pathology at Karolinska Institutet, is investigating how to tune different drug treatments in the clinical situation. The aim is to give doctors better opportunities to make wise choices for each patient—as effectively as possible, with as few side effects as possible. Everything is investigated with classic clinical trials, where patients are randomized between different treatment options and followed over time. Many of the studies are conducted in large international collaborations.

Promising immunotherapy

A specific example is studies on the immunotherapy Keytruda, with the active substance pembrolizumab. This drug was previously given in the breast cancer field only to women with metastatic triple-negative breast cancer, where the disease has sent distant metastases to, for example, the bones, lungs or liver. Disseminated breast cancer is currently incurable, so the aim is to slow down the disease and prolong life.

Triple-negative breast cancer means that the cells lack receptors for estrogen, progesterone and HER2. Because many treatments are designed to block these receptors, there are fewer drugs available for triple-negative breast cancer, which is often more aggressive and in many cases affects younger women.

In triple-negative breast cancer, treatment usually starts with chemotherapy to shrink the tumor before surgery. Theodoros Foukakis has led the Swedish part of a study that has tested a new approach to the treatment given before surgery. In this study, women were randomized into two groups: half received chemotherapy with the addition of the immunotherapy pembrolizumab, and the rest received chemotherapy and a placebo. After surgery, the women continued treatment with either immunotherapy or placebo.

Five years later, nearly 19 of those who received additional immunotherapy had relapsed. The corresponding figure for those who only received chemotherapy was 28. A difference of 9 percentage points. And most of the relapses were not a new tumor in the breast, but spread disease with distant metastases.

Roughly speaking, just under a thousand women per year are diagnosed with triple-negative breast cancer in Sweden. This means that just under a hundred women avoid relapse if immunotherapy is included in the treatment given before surgery. This treatment approach is now clinical practice in Sweden for this patient group.

"That 9% is very important. Many of those who relapse cannot be cured," says Theodoros Foukakis.

Another part of his research involves finding biomarkers in patients. Again, the goal is to understand who benefits from a particular treatment.

"This is research that pharmaceutical companies are not always interested in doing. But in the clinic, we need to be able to identify the different subgroups that will or will not benefit from different drugs so that we can make the right choice. Otherwise, patients risk receiving drugs that do not help them but only cause side effects, says Theodoros Foukakis.

Provided by Karolinska Institutet

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• Review Article
• Published: 21 July 2023

The global burden of lung cancer: current status and future trends

• Amanda Leiter   ORCID: orcid.org/0000-0001-9072-5512 1 ,
• Rajwanth R. Veluswamy 2 , 4 &
• Juan P. Wisnivesky 3  

Nature Reviews Clinical Oncology volume  20 ,  pages 624–639 ( 2023 ) Cite this article

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• Cancer epidemiology
• Health policy
• Non-small-cell lung cancer
• Public health

Lung cancer is the leading cause of cancer-related death worldwide. However, lung cancer incidence and mortality rates differ substantially across the world, reflecting varying patterns of tobacco smoking, exposure to environmental risk factors and genetics. Tobacco smoking is the leading risk factor for lung cancer. Lung cancer incidence largely reflects trends in smoking patterns, which generally vary by sex and economic development. For this reason, tobacco control campaigns are a central part of global strategies designed to reduce lung cancer mortality. Environmental and occupational lung cancer risk factors, such as unprocessed biomass fuels, asbestos, arsenic and radon, can also contribute to lung cancer incidence in certain parts of the world. Over the past decade, large-cohort clinical studies have established that low-dose CT screening reduces lung cancer mortality, largely owing to increased diagnosis and treatment at earlier disease stages. These data have led to recommendations that individuals with a high risk of lung cancer undergo screening in several economically developed countries and increased implementation of screening worldwide. In this Review, we provide an overview of the global epidemiology of lung cancer. Lung cancer risk factors and global risk reduction efforts are also discussed. Finally, we summarize lung cancer screening policies and their implementation worldwide.

Lung cancer is the leading cause of cancer death globally, with incidence and mortality trends varying greatly by country and largely reflecting differences in tobacco smoking trends.

Cigarette smoking is the most prevalent lung cancer risk factor, although environmental exposures, such as biomass fuels, asbestos, arsenic and radon, are all important lung factor risk factors with levels of exposure that vary widely across the globe.

Lung cancer incidence and mortality rates are highest in economically developed countries in which tobacco smoking peaked several decades ago, although these rates have mostly now peaked and are declining.

Reductions in lung cancer mortality in economically developed countries reflect decreased incidence (mirroring declines in tobacco smoking) and improvements in treatment of patients with advanced-stage disease, including immunotherapies and targeted therapies.

In low-income and middle-income countries at the later stages of the tobacco epidemic, both lung cancer incidence and mortality are increasing, thus highlighting the importance of tobacco mitigation policies for reducing the global burden of lung cancer.

Low-dose CT-based lung cancer screening reduces lung cancer mortality, although adoption of lung cancer screening programmes has been slow, with limited uptake compared with other cancer screening programmes.

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Amanda Leiter

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Rajwanth R. Veluswamy

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Juan P. Wisnivesky

Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA

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Leiter, A., Veluswamy, R.R. & Wisnivesky, J.P. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol 20 , 624–639 (2023). https://doi.org/10.1038/s41571-023-00798-3

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A Review of Colorectal Cancer in Terms of Epidemiology, Risk Factors, Development, Symptoms and Diagnosis

Tomasz sawicki.

1 Department of Human Nutrition, Faculty of Food Sciences, University of Warmia and Mazury in Olsztyn, Słoneczna 45F, 10-719 Olsztyn, Poland; [email protected] (M.R.); [email protected] (A.D.); [email protected] (E.N.); [email protected] (K.E.P.)

Monika Ruszkowska

Anna danielewicz, ewa niedźwiedzka, tomasz arłukowicz.

2 Department of Internal Medicine, School of Medicine, Collegium Medicum, University of Warmia and Mazury, 10-900 Olsztyn, Poland; lp.nytzslo.ssw@zciwokulrat

Katarzyna E. Przybyłowicz

Simple summary.

According to the available data, colorectal cancer (CRC) is one of the most common malignant neoplasms. Depending on the location, type of cancer or gender, it is ranked 2nd to 4th in terms of incidence in the world. CRC, year by year, shows an increasing tendency in terms of both morbidity and deaths. Many factors may be responsible for the development of this disease, including genetic and environmental factors. Considering all the aspects, we made efforts to systematize the available literature data in terms of epidemiology, risk factors, type and nature of symptoms, development stages, available and future diagnosis of colorectal cancer.

This review article contains a concise consideration of genetic and environmental risk factors for colorectal cancer. Known risk factors associated with colorectal cancer include familial and hereditary factors and lifestyle-related and ecological factors. Lifestyle factors are significant because of the potential for improving our understanding of the disease. Physical inactivity, obesity, smoking and alcohol consumption can also be addressed through therapeutic interventions. We also made efforts to systematize available literature and data on epidemiology, diagnosis, type and nature of symptoms and disease stages. Further study of colorectal cancer and progress made globally is crucial to inform future strategies in controlling the disease’s burden through population-based preventative initiatives.

1. Introduction

The most common cancer diagnosed in both sexes is lung cancer (11.6% of the total cases), followed by breast cancer in women (11.6%) and prostate cancer in men (7.1%). Colorectal cancer (CRC) is third in terms of recognition (6.1%) and second in terms of mortality (9.2%). It is estimated that by the year 2035, the total number of deaths from rectal and colon cancer will increase by 60% and 71.5%, respectively [ 1 ]. These figures may differ from country to country depending on the degree of economic development. Therefore, the disease is widely recognized as a marker of the country’s socioeconomic development [ 2 ]. The increase in morbidity is also influenced by lifestyle, body fatness and dietary patterns [ 3 ]. There is convincing evidence that physical activity has a protective effect. The risk of developing the disease is increased by more frequent red and processed meat and alcohol drinks [ 2 , 4 ]. The progress of civilization and economic development, apart from improving socioeconomic conditions, also causes a change in dietary patterns, referred to as the westernization of the lifestyle. This means higher consumption of animal fats, processed meats, refined grains or sweets, a low supply of dietary fibers, fruits, vegetables and low physical activity. The occurrence of overweight or obesity is often the result of such a lifestyle [ 5 ]. Overweight and obesity are associated with an increased risk of many civilization diseases. Visceral obesity has been reported to adversely affect the prognosis of CRC in men [ 6 ]. About a quarter of a contributor to genetic predisposition. The development time of CRC usually lasts from several to several years; therefore, it is very important to diagnose it early in developing the disease. Based on follow-up examinations and nutrition prevention based on a balanced diet, secondary prevention is also important [ 7 ].

Considering all the aspects, we made efforts to systematize the available literature data in terms of epidemiology, risk factors, type and nature of symptoms, stages of development and available diagnosis of colorectal cancer.

2. Epidemiology

Colorectal cancer is the third most popular occurring cancer in men and the second most commonly occurring cancer in women. There were over 1.9 million new cases in 2020 [ 3 , 8 ]. Colorectal cancer is the second most common cause of death from cancer, estimated to be responsible for almost 935,000 cancer deaths [ 3 ]. Globally it is one of the cancers whose incidence is increasing comprising 11% of all cancer diagnoses [ 9 ]. According to GLOBOCAN 2020 data there is a broad geographic variation in CRC incidence and mortality among various countries of the world ( Figure 1 ) [ 10 , 11 ]. It has been recognized that the most significant increase in CRC incidence and mortality occurs in medium and high human development index (HDI) countries that are adopting the “western” way of life [ 9 , 10 ]. Developed countries are at the highest risk of colon cancer. Obesity, sedentary lifestyle, red meat consumption, alcohol and tobacco are considered the driving factors behind the growth of CRC [ 3 , 8 , 9 , 10 , 11 ]. Therefore, colorectal cancer is a disease of developed countries with a western lifestyle [ 12 , 13 ]. Factors that influence life expectancy, including health-related behaviors (smoking, obesity and exercise) and social factors (education, income and government expenditure on health), profoundly impact cancer development. Life expectancy levels must be considered when developing strategies to prevent and treat cancer [ 12 , 13 ]. Interesting data comes from study conducted that in 2007 to 2016, 2006 to 2015 or 2005 to 2014, depending on the data’s availability, colon cancer incidence increased in 10 of 36 countries analyzed (all in Asia or Europe); India had the most significant increase, followed by Poland [ 3 , 11 ]. All 10 of these countries have medium to high (HDI) scores. Six countries had a decrease in colon cancer incidence; these countries had the highest HDI scores; the United States had the most significant reduction, followed by Israel. Seven countries (including all countries from Northern America) had a decrease in incidence among persons older than 50 [ 9 , 10 , 11 ]. Eight countries had an increase in colon cancer incidence among persons younger than 50 years, including the United Kingdom and India. Countries with a decreased or stable incidence among persons 50 years or older but a significant increase in persons younger than 50 years included Germany, Australia, the United States, Sweden, Canada and the United Kingdom [ 8 , 9 , 10 , 11 ]. The decline in the incidence of CRC was recorded only in Italy among people under the age of 50. Among women, 12 of 36 countries (all from Asia and Europe) had an increase in colon cancer incidence, and seven countries had a decrease; India had the most significant growth, followed by Slovenia [ 9 , 10 ]. Many works have attracted attention that colorectal cancer survival depends on the stage at which it is diagnosed, with later-stage diagnosis having lower survival [ 2 , 3 , 8 , 9 ]. The five-year survival rate is 90 percent for colorectal cancers diagnosed at an early stage compared with 13 percent for those diagnosed later. At age 0–74, the cumulative risk of dying from colon cancer is 0.65% among men and 0.45% among women [ 3 , 8 , 11 ]. Age-standardized (world) mortality rates per 100,000 of CRC in both sexes is 8.9 [ 3 ].

Standardized incidence and mortality rates for CRC for both sexes in 2020, per 100,000.

In recent years, the global burden of CRC will increase by 60%, to over 2.2 million new cases and 1.1 million deaths by 2030. Such a significant increase will be the result of economic development, an economic transformation consisting in the transition from low-to-medium-HDI nations and generational changes in developed countries. Many research studies emphasize that this increase is also the result of environmental changes, such as a more sedentary lifestyle, abnormal bony weight (obesity), consumption of highly processed food, alcohol, red meat consumption and an increase in overall life expectancy [ 2 , 9 , 10 ]. With the best scientific understanding in mind, an updated study of the current patterns and temporal trends of CRC from a global perspective is critical to developing future strategies for prevention and treatment programs to reduce disease incidence. Many research works emphasize the need to allocate resources for health education focused on CRC risk factors and to formulate screening programs using the latest scientific reports in the aspect of public health.

3. Risk Factors

Multiple factors have been implicated in the development of colorectal cancer ( Figure 2 ). It was demonstrated that individuals are at increased risk for CRC if they (or their relatives) have had cancer, a history of colon polyps, inflammatory bowel diseases, diabetes mellitus or cholecystectomy. Lifestyle factors also play important roles in CRC etiology. The evidence shows that overweight and obesity, physical inactivity, cigarette smoking, alcohol consumption and inappropriate dietary patterns (a diet low in fiber, fruits, vegetables, calcium and dietary products and high in red and processed meat) increase CRC risk. In addition, gut microbiome, age, gender and race and socioeconomical status are known to influence colorectal cancer risk.

The main risk factors associated with colorectal cancer.

3.1. Family and Personal Medical History

3.1.1. family history and genetics.

A family history of colorectal cancer significantly increased the risk of developing colorectal cancer. This phenomenon shares both inherited genetic predisposition and lifestyle factors. The information relevant for future colorectal cancer occurrence, among other, include: (i) the generational distance of the relatives to the individuals at risk; (ii) the age at which the first-degree relatives developed colorectal cancer; (iii) the number of family members diagnosed with colorectal cancer; (iv) family co-occurrence of other neoplasms (e.g., endometrial, ovarian and urinary tract, pancreatic) and (v) personal history of cancer. Previous studies indicated that people with one affected first-degree relatives (parents, siblings and children) have, on average, two times higher risk of CRC in comparison to those with no family history. The risk of CRC development is significantly higher if a relative is diagnosed before the age of 60. Moreover, a higher number of affected relatives (not only first-degree but also second- and third-degree) also increases the disease risk [ 14 , 15 , 16 , 17 ].

It is estimated that 2–8% of colorectal cancer cases arise as a result of inherited syndromes. The two most common hereditary syndromes that predispose for colorectal cancer development are hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, and familial adenomatous polyposis coli (FAP). HNPCC is an autosomal dominant disease caused by mutations in genes known as mismatch repair errors. Proteins encoded by these genes are responsible for reaper errors in DNA that occur during cell division. Most cases of HNPCC are associated with mutations in MLH1 and MSH2 genes. However, there are several other genes mutations in which give rise to HNPCC (e.g., MSH6, MLH3, TGBR2, PMS1 and PMS2). Patients with HNPCC have about 20% risk of developing CRC by the age of 50 and about 80% risk of developing CRC by the age of 85 [ 15 , 18 , 19 , 20 , 21 ].

Similar to HNPCC, FAP also presents an autosomal dominant pattern of heredity. It is caused by adenomatous polyposis coli (APC) gene defects. APC is classified as a tumor suppressor gene. It encodes a protein that plays a significant role in regulating DNA replication and cell division. Individuals with FAP start to develop hundreds or even thousands of colon polyps in their mid-teens and, with high-probability, most of these colon polyps evolve into cancer. It is assumed that almost all patients with the earlier unrecognized and untreated FAP syndrome will be diagnosed with colorectal cancer before the age of 35–40 [ 19 , 20 , 21 , 22 ].

The increased risk of CRC development is also linked with the occurrence of Peutz-Jeghers syndrome, Juvenile polyposis syndrome, PTEN hamartoma tumors syndrome and MUTYH-associated polyposis (MAP) [ 21 ].

3.1.2. Inflammatory Bowel Disease (Crohn’s Disease; Ulcerative Colitis)

Inflammatory bowel disease (IBD) is ranked as the third-highest risk condition for the development of colorectal cancer, behind HNPCC and FAP. IBD is a group of chronic and incurable diseases, which affect the immune system of the gastrointestinal tract and, in consequence, lead to the development of uncontrolled inflammation. The two major forms of IBD are Crohn’s disease and ulcerative colitis. The etiology of IBD is unknown, it is considered that the development of IBD is a result of interactions between genetic, immunological and environmental factors [ 20 , 23 ]. Due to the fact that chronic inflammation promotes tumor growth and progression, individuals with IBD have about 2–6 times higher risk of developing CRC in comparison to healthy individuals. The risk of CRC increases with the duration of IBD and the anatomic extent and severity of the disease [ 14 , 24 , 25 ].

3.1.3. Colon Polyps

Colon polyps (precancerous neoplastic lesions) are defined as an abnormal growth of tissue projecting from a mucous layer of the colon. They are histologically classified into two main categories: non-neoplastic (hamartomatous, hyperplastic and inflammatory polyps) and neoplastic (adenomatous, Figure 3 ). The adenomatous polyps are of great importance because they harbor the potential to become malignant. It is estimated that about 95% of colorectal cancer is developed from adenomatous polyps. Despite the fact that almost all cancer arises from adenomas, it is estimated that only about 5% of polyps progress to colorectal cancer [ 16 , 26 ]. The period for the transition of adenomatous polyps into invasive adenocarcinoma is 5–15 years and the risk of malignant transformation increases with polyp size, degree of dysplasia and the age of individuals. Polyps greater than 1–2 cm in diameter, a high degree of dysplasia and increasing age are unfavorable prognostic factors. Due to the fact that approximately 40% of people at the age of 50 or older have one or more adenomatous polyps, it is of great importance to identify these polyps and remove them prior to cancer transition [ 14 , 26 ].

Representative histopathological appearance of adenomatous ( A , B ) and serrated ( C , D ) changes in the colon.

3.1.4. Diabetes Mellitus

Diabetes mellitus is a metabolic disorder characterized by chronic hyperglycemia, which results from defects in insulin secretion and/or action. It is estimated that around 460 million people globally are currently suffering from diabetes and the number will continue to grow. Epidemiological data indicate that diabetes is an independent risk factor for several gastrointestinal cancers, including colorectal cancer [ 27 , 28 ]. Individuals with type 2 diabetes have about two-three times greater risk of developing colorectal cancer in comparison to the non-diabetic population [ 29 , 30 ]. The development of colorectal cancer is thought to be related to an increase in insulin concentration and an inflammatory condition associated with the disease. Hyperinsulinemia may contribute to colorectal cancerogenesis directly by stimulating colonic cell proliferation and indirectly by increasing the level of insulin-like growth factor 1 (IGF-1). IGF-1 is a mitogenic factor that enhances cell growth and decreases cell death [ 27 , 31 ]. Moreover, chronic inflammation associated with diabetes favors carcinogenesis, malignant transformation, tumor growth, invasion and metastasis through the action of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-6 (Il-6) [ 31 , 32 ].

3.1.5. Cholecystectomy

The possible association between cholecystectomy, the surgical removal of the gallbladder from the body and subsequent colorectal cancer incidence has still not been firmly established or refuted. The results from some studies indicated an increased risk of CRC development after cholecystectomy [ 33 , 34 , 35 ], whereas others have reported no increased risk [ 36 , 37 , 38 ]. The possible increased risk of CRC after cholecystectomy is thought to be associated with changes in the secretion and composition of bile acids. Under physiological conditions bile acids are released periodically in response to food intake. In the absence of a gallbladder, there is a continuous flow of bile to the intestine, which results in increased bacterial biotransformation of bile acids into secondary bile acids. The secondary bile acids have the potential to generate reactive oxygen and nitrogen species, disturb the cell membrane and induce DNA damage and apoptosis in the colonic mucosa cells, which increase the risk of developing colon carcinomas [ 39 , 40 ].

3.2. Lifestyle

3.2.1. dietary patterns.

• Diet high in red and processed meat

According to the International Agency for Research on Cancer Group, red meat and processed meat were classified as probably carcinogenic to humans (Group 2A) and carcinogenic to humans (Group 1), respectively. Red meat is defined as the meat derived from the muscle of farm animals (e.g., beef, lamb, game and pork). Processed meat refers to the meat that has been preserved by curing, salting, smoking or adding chemical preservatives in order to improve favor or extend the shelf life. Studies have shown that regular consumption of red and processed meat is an important risk factor for the development of colorectal cancer [ 20 , 41 ]. It is estimated that the risk of CRC may increase by about 17% for every 100 grams portion of red meat and by approximately 18% for every 50 grams of processed meat eaten daily [ 42 , 43 , 44 ]. The exact mechanism by which consumption of red and processed meat may contribute to the development of colorectal cancer is still under investigation. Several factors that are believed to influence the occurrence of cancer are heterocyclic amines (HACs), polycyclic aromatic hydrocarbons (PAHs) and N-nitroso compounds (NOCs)—harmful substances that may be produced during high-temperature or open-fire cooking of meat (e.g., pan-frying, grilling and roasting). HACs are formed during the specific reaction of free amino acids, carbohydrates and creatinine or creatine (substances found in muscle). PAHs, in turn, are formed when fat and juice from meat come into contact with open flames. The smoke that contains PAHs attaches to the surface of the cooked meat. HACs and PAHs are considered genotoxic substances that have the potential to cause point mutations (deletions, insertions and substitutions) and, in consequence, initiate the process of carcinogenesis. Similarly, NOCs (nitrosamine and nitrosamide) are potent carcinogenic agents that can react with DNA. These substances are synthesized from amines or amides and oxides of nitrogen (nitrites or nitrates, i.e., substances used as a food additive to inhibit the growth of bacteria and gives the meat the desirable cured) during high-heat cooking of processed meat [ 45 , 46 ]. The other factor that is believed to contribute to the malignant transformation of colon cells is heme, an iron-containing porphyrin presents in large amounts in red meat. It was demonstrated that heme increases oxidative stress and induce lipid peroxidation of intestinal cells. Reactive oxygen species contribute to DNA damage and gene mutations. Reactive lipid peroxides, in turn, exert a cytotoxic effect on epithelial cells. The damage of the cell surface results in hyperproliferation of the cells and leads to epithelial hyperplasia, which may evolve to dysplasia and cancer. In addition, heme irons stimulate the endogenous formation of the above-mentioned NOCs and induce alternation in the gut microbiota leading to a state of dysbiosis [ 5 , 41 , 44 ]. It should be also emphasized that consumption of high-fat red and processed meat contributes to obesity, insulin resistance and an increase of bile acid secretion, which acts as an aggressive surfactant for the mucosa and increase the risk of developing colorectal cancer.

• Diet low in fiber, fruits and vegetables

It was shown that the high consumption of dietary fiber could reduce the risk of colorectal cancer development by up to 50% [ 14 ]. However, currently available results of epidemiologic studies not unequivocally support the protective effects of fiber against CRC and the precise mechanism of anticancer fiber action has not been clearly established. The potential mechanism of the protective effect of fiber consumption on CRC development includes: (i) reduction of transit time for stool throughout the colon and, in consequence, reduction of contact between potential carcinogenic substances and colonic epithelium, (ii) increase in the amount of water in fecal content and thus dilution of carcinogens and procarcinogens present in fecal, (iii) binding sterols and bile acids metabolites, which may be implicated in carcinogenesis, and (iv) stimulation the growth of beneficial gut microbiota, which, in turn, ferment fiber and produce short-chain fatty acids—substances suggested to exert tumor-suppressive effects. Therefore, dietary guidelines recommend people consume at least 20–30 g of fiber per day [ 5 , 16 , 17 , 41 ]. Naturally great sources of fiber are fruits and vegetables. In addition to fiber intake, consumption of fruits and vegetables provides a large number of bioactive compounds, such as vitamins, minerals, folate, plant sterols and protease inhibitors. Many of these compounds exhibit potent antioxidant and anti-inflammatory properties, which could inhibit DNA and cellular damage. The results from several studies demonstrated that a high intake of fruits and vegetables may be linked with a lower CRC risk development [ 17 , 24 , 41 ].

• Diet low in calcium, vitamin D and dairy products

According to the World Cancer Research Fund/American Institute for Cancer Research [ 41 ], the high consumption of dairy products (in particular milk) is probably inversely associated with the risk of developing colorectal cancer. The suggested protective effect of dairy products has been largely attributed to their content of calcium. It was demonstrated that calcium binds secondary bile acids and fatty acids diminishing their ability to modify intestinal mucosa and, in consequence, limiting their carcinogenic potential. Moreover, calcium was found to inhibit proliferation and to induce apoptosis of tumor cells and reduce distinct patterns of mutation in proto-oncogene KRAS [ 5 , 41 , 47 ]. In addition to calcium, the other milk component, i.e., vitamin D is also suggested to play a beneficial role against CRC development. The roles of vitamin D and calcium are closely related since the primary function of vitamin D is the maintenance of calcium homeostasis by enhancing its intestinal absorption. It is hypothesized that the anticancer effect of vitamin D may be a result of the increased level of serum calcium concentration. It should be emphasized, however, that vitamin D exerts many other physiological functions that may play an important part in cancer control. The results of the studies showed that vitamin D alters the expression of a variety of genes involved in the regulation of growth, proliferation, differentiation and apoptosis of epithelial cells. Moreover, it exhibits anti-inflammatory action, improved immune function and inhibits angiogenesis [ 48 , 49 ]. Due to the fact that the major source of vitamin D for humans is skin exposure to sunlight, there are some studies to determine if the distribution of colorectal cancer incidence depends on amounts of natural light. It was demonstrated the colorectal cancer mortality rates were higher in the northern regions of the United States and Europe. It is assumed that people who live at higher latitudes are exposed to less amount of solar ultraviolet-B dose, synthesize less vitamin D and therefore have a higher risk of developing and die from colorectal cancer [ 48 ]. On the other hand, the results of the study performed in Norway showed that there is no significant north–south gradient for the death rate for colon cancer. However, the survival rate of colon cancer depended on the season of diagnosis and was the lowest in the cancers diagnosed in the autumn. Recent meta-analyses of prospective cohorts demonstrated that, regardless of geographic location, higher serum vitamin D level was related to a statistically significant, substantially lower colorectal cancer risk in women and non-statistically significant lower risk in men [ 50 ]. According to World Cancer Research Fund/American Institute for Cancer Research [ 41 ], the evidence for vitamin D was limited and there is a need to perform research assessing the anticancer activity of vitamin D.

3.2.2. Overweight and Obesity

A condition of abnormal or excessive fat accumulation (overweight and obesity) is a convincing risk factor for the development of colorectal cancer. Overweight/obese men and women have about 50% and 20% greater risk of developing colorectal cancer in comparison to people with normal weight, respectively. It is estimated that an overall CRC risk increase by 3% for every five kilograms of weight gain [ 17 , 20 ]. The mechanisms underlying the induction of carcinogenesis in overweight/obese people are not fully understood and still under intense study. Adipose tissue is an endocrine organ that plays a crucial role in the regulation of energy intake and inflammatory response. It was found that abnormal or excessive fat accumulation causes alternations in adipose tissue hormone and cytokine secretions. Adipose tissue of overweight/obese people release more factors (e.g., leptin, resistin, TNF-α, IL-1, IL-6, IL-7 and IL-8), which are known to exhibit mitogenic effects on epithelial cells, inhibit apoptosis of the cells, promote oxidative stress, suppress immune response and reduce the activity of IGF-1 axis and have been associated with cancer development and progression [ 5 , 41 , 51 ].

3.2.3. Physical Inactivity

Epidemiological data indicate that an increasing colorectal cancer incidence in developed and developing countries may be the result of a sedentary lifestyle. It is estimated that physically inactive people have up to 50% higher risk of developing colorectal cancer in comparison to the most physically active ones [ 17 , 52 ]. Regular physical exercises have been shown to improve immune system function, reduce inflammation, reduce stress, optimize metabolic rate, help regulate hormone level and prevent obesity and, as a result, may help protect against cancer development [ 47 ].

3.2.4. Cigarette Smoking

Tobacco smoke is an established risk factor for the development of many types of cancer, including colorectal cancer. The results of the studies indicated that people who smoke cigarettes have to 2–3-fold increase risk for developing CRC in comparison to non-smokers and the risk increases with dose and duration of exposure [ 31 ]. In addition, it is considered that cigarette smoking is attributed to up to 12% of colorectal cancer deaths [ 16 ]. Tobacco smoke contains a mixture of thousand chemicals, over 60 of which are well-established carcinogens (e.g., N-nitrosamines, polycyclic aromatic hydrocarbons, aromatic amines, aldehydes and metals) that are known to damage DNA. Mutations in colorectal epithelial cells may lead to polyposis development, which, in turn, may transit into invasive adenocarcinoma [ 53 ].

3.2.5. Alcohol Consumption

Alcohol intake is one of the major contributors to colorectal cancer development. It is estimated that the consumption of 2–3 drinks daily increases the risk of CRC by about 20%, whereas drinking more than three alcoholic beverages increases this risk by about 40% [ 17 , 20 ]. Individuals who are used to drink four and more drinks every day increase their chance of developing colorectal cancer for up to 52% [ 54 ]. To date, the various mechanism by which alcohol may induce carcinogenesis have been proposed. They include the production of reactive oxygen species and nitrogen species (during the oxidative metabolism of ethanol), production of mutagenic acetaldehyde (the first metabolite of ethanol), depletion of S-adenosylmethionine (epigenetic alternations), inactivation of the tumor suppressor genes, hormonal imbalance, reduction in folate concentration and impairment of retinoic acid metabolism [ 47 , 55 ].

3.3. Others

3.3.1. gut microbiota.

Recently, a growing number of studies indicated that gut microbiota may be a key factor that contributed to the development of many pathological processes, including cancer. The gut microbiota (microbiome) comprises a large population of diverse microorganisms (bacteria, viruses, fungi and protozoa) inhabiting the gastrointestinal tract of humans. In healthy people, the microbiome is involved in nutrient metabolism and absorption, drug metabolism and elimination of xenobiotics. In addition, normal gut microbiota participates in the maintenance of intestinal barrier integrity, protects against pathogens and plays an important role in immunomodulation. According to the latest research that explored the microbiome of the individuals with colorectal cancer, alternation in the composition and functionality of the normal gut microbiota may lead to initiation, promotion and progression of this cancer. It was demonstrated that toxic metabolites of bacteria cause DNA damage, affect cell cycles, stimulate immune response and lead to disturbance of the intestinal barrier function. As a result, impaired intestinal microbiota homeostasis contributes to the development of the microenvironment favorable to develop colorectal cancer [ 56 , 57 , 58 , 59 , 60 ].

Due to the fact that about 90% of all new cases of colorectal cancer occurring in individuals over 50 years old, older age is considered to be one of the most significant factors influencing the risk of developing colorectal cancer [ 14 , 16 ]. It is estimated that people after the age of 65 have about three times greater risk to develop colorectal cancer in comparison to those at the age of 50–64 and about 30 times greater risk than people at the age of 25–49 [ 20 ]. The average age at diagnosis is 68 and 72 years old for men and women, respectively. The fact that colorectal cancer is the age-related disease is particularly evident in the developed countries where the rate of colorectal cancer is the highest. The number of colorectal cancer incidence in these countries is associated, among others, with longer life expectancy and, in consequence, increase number of old people in the population [ 61 ]. It should be emphasized, however, that the results of the newest studies indicated that the incidences of colorectal cancer rise among young adults (20–49 years old) in the United States and Europe [ 62 , 63 ]. Currently, it is recommended to begin screening for colorectal cancer in adults aged more than 50 years. According to the authors of the studies, if the mentioned trend continues, screening guidelines should be reconsidered.

3.3.3. Gender and Race

According to the American Cancer Society, men have about 30% higher risk of developing colorectal cancer in comparison to women. In addition, men who are diagnosed with colorectal cancer have a worse prognosis and approximately 40% higher mortality compared to women [ 17 ]. On the other hand, women are more prone to develop right-sided colon cancer, which is often diagnosed at a more advanced stage and seemed more aggressive than left-sided tumors [ 64 , 65 ]. The reasons for sex disparity are not fully understood, it is considered that they may be related to the differences in the exposure to risk factors (e.g., alcohol and tobacco), dietary patterns and sex hormones [ 17 , 47 ].

The incidence of colorectal cancer varied substantially by race also. The non-Hispanic Black individuals experience one of the highest incidence rates of all racial groups. It is estimated that colorectal cancer incidence rate in non-Hispanic Blacks is approximately 50% higher than in Asians/Pacific Islanders and about 20% higher than in non-Hispanic Whites [ 17 , 66 ].

3.3.4. Socioeconomics Factors

It is believed that people with low socioeconomic status (SES) generally have a higher risk of developing cancer than those with high SES. This may be explained in part by limited access to health care services and high-quality treatment resources and unhealthy dietary habits, sedentary lifestyle and smoking in the low socioeconomic status population [ 16 , 67 ]. It should be emphasized, however, that the results concerning the association of SES with the incidences of colorectal cancer are inconsistent. In North America, people with low SES exhibited a higher incidence of colorectal cancer in comparison to people with high SES, contrary, in Europe, high SES groups often show a higher risk of developing colorectal cancer. Therefore, there is a need to perform additional studies in order to establish the impact of socioeconomic status on colorectal cancer occurrence [ 68 ].

4. Development Factors

The formation of CRC consists of the stages of initiation, promotion and progression. Initiation involves irreversible genetic damage that predisposes the intestinal mucosa’s affected epithelial cells to subsequent neoplastic transformation [ 69 ]. In the promotion phase, the initiated cells multiply, generating abnormal growth (cancer). In contrast, benign cancer cells turn into malignant ones during the progression stage and acquire aggressive features and metastatic potential [ 24 ]. A crucial part of most CRC carcinogenesis steps is the presence of a benign precursor lesion, defined as a polyp (defined as abnormal growth on the colon mucosa growing in its lumen). Another type of lesions identified in the large intestine lumen is adenomatous polyps (adenomas, Figure 4 ) and serrated polyps, which are the direct precursors of most cancers [ 20 , 70 ]. Advanced adenomas (≥1 cm in diameter) with or without diversity have a significantly higher risk of cancer progression (from 30 to 50%) than non-advanced adenomas (1%). Moreover, advanced adenomas characterizing the higher transition rates to cancer, increasing with age [ 71 , 72 ]. The other changes in the gut wall, such as polished polyps, represent a group of heterogeneous lesions, which include: hyperplastic polyp, traditional serrated adenoma, sessile serrated adenoma and mixed polyp [ 73 ]. They combine the toothed morphological appearance of hyperplastic polyps and dysplastic features of adenomas, and these changes are precursors to approximately 10–15% of sporadic CRC. However, the most common lesion present in the gut is a hyperplastic polyp (80–90%) [ 53 ]. The research showed that the hyperplastic polyps (especially large and/or in the proximal colon) could pass in the CRC as part of a serrated pathway through traditional serrated adenoma or serrated sessile adenoma [ 74 ]. Undoubtedly, the process of CRC carcinogenesis is quite slow, starting with a slight inflammation, then through the development of adenomatous polyps in the epithelium, and finally, the development of adenocarcinoma ( Figure 5 ) [ 75 ]. Moreover, the process is driven by the accumulation of mutations and genetic changes and takes 10–15 years, but maybe faster in some conditions, e.g., in patients with Lynch syndrome [ 76 ].

Selected endoscopic images of adenomas and CRC at different stages. ( A )—Tubular adenoma; ( B )—tubulo-villous adenoma; ( C )—sedentary serrated adenoma (SSA) without dysplasia; ( D )—tubular adenocarcinoma, grade 1 and ( E )—tubular adenocarcinoma, grade 2.

Representative histopathological appearance of adenocarcinoma in the colon.

About 20% of CRC is associated with hereditary syndromes such as familial adenomatous polyposis (FAP), Lynch syndrome (HNPCC), mutation-related polyposis MUTYH (MAP) and hamartomatous polyposis syndromes (Peutz-Jeghers, juvenile polyposis and Cowden disease) [ 51 , 77 , 78 ]. In the case of HNPCC, one allele of the DNA repair gene, while in FAP, one allele of the adenomatous polyposis tumor suppressor (APC) gene is inactivated by the germline [ 77 ]. Moreover, about 80% of people with FAP have an affected parent, including about 20% of cases are de novo mutations. It is estimated that 95% of people with FAP develop adenoma as early as 35 [ 78 ]. A colectomy is then indicated, recommended when more than 20–30 adenomas have been designed, or multiple adenomas with advanced histology have developed. HNPCC is associated with pathogenic variants of the MLH1, MSH2, MSH6, PMS2 and EPCAM genes, and is also characterized by an increased risk of CRC, the pathological feature of which is the presence of mucinous adenocarcinoma (lifetime risk at 52–82%, mean age at diagnosis 44–61 years) [ 23 , 79 ]. Moreover, this neoplasm may predispose to asynchronous or metachronous colorectal neoplasm [ 68 ].

CRC may also arise in the inflammatory pathway in patients with inflammatory bowel disease, particularly ulcerative colitis. In these patients, from the absence of dysplasia, through dysplasia for an indefinite period, low-grade dysplasia, to high-grade changes towards neoplastic transformation, finally, CRC occurs [ 24 ].

The most commonly affected genes in the CIN pathway (the chromosomal instability pathway) are APC, p53 and K-ras, which are responsible for the adenocarcinoma sequence pathway. Changes within these genes lead to mutational activation of oncogenes or inactivation of tumor suppressors, which consequently causes malignant transformation. CIN pathway is responsible for 70–85% of all CRC cases [ 80 , 81 , 82 ]. Apart from the mechanisms related to chromosomal instability (CIN) and microsatellite instability (MSI—microsatellite instability), a third one should be mentioned, related to the methylator phenotype (CIMP—CpG island methylator phenotype) [ 83 , 84 ]. It is associated with hypermethylation of numerous gene promoters (including MLH1), the V300E mutation in the BRAF gene, and loss of TP53 and p16 functions. These disorders cause silencing of suppressor genes and thus disturbances in the MMR system’s functioning, the occurrence of MSI and the state of hypermutation. This mechanism is most often observed in the development of serrated architectural lesions, most often in women in the colon’s proximal part [ 85 ].

As mentioned above, CRC is a non-homogeneous disease entity. Individual cases differ in location, degree of histological malignancy or the type of neoplasm. However, the most exciting thing is the multilevel molecular complexity. The consensus developed in 2015 by the CRC Subtyping Consortium identified four molecular subtypes of colorectal cancer (CMS): CMS1—MSI-immune activation, CMS2—canonical, CMS3—metabolic and CMS4—mesenchymal. The classification is of practical importance: individual subtypes differ in their clinical course and respond differently to chemotherapeutic and biological treatment. This may determine the selection of the optimal, individualized therapeutic strategy for each patient and is also a helpful predictive and prognostic tool. Perhaps the most promising is the application of these phenomena to molecular screening for colorectal cancer [ 86 ].

In 10% of all colorectal cancers, serrated adenocarcinomas develop by replacing adenomatous polyps with serrated polyps on the so-called serrated lesion pathway, showing the presence of the BRAF mutation and epigenetic silencing of various genes, but without APC gene involvement, as is the case in other pathways. Another mechanism leading to CRC is microsatellite instability (MSI), caused by the disruption of DNA repair genes [ 44 , 80 , 87 ]. The inherited genetic predisposition and exposure to environmental factors may work together to form adenomas and cancer based on synergy [ 44 ]. However, most CRCs are sporadic, meaning that patients do not have a genetic burden, and the development of this type of cancer is linked to lifestyle and environmental factors. Moreover, long-term exposure to carcinogens may promote oxidative stress. Oxidative stress can be increasing DNA damage by generating sequential accumulation of somatic mutations, leading to genome instability [ 44 ].

5. Symptoms

CRC may be suspected when some of the lower gastrointestinal (GI) symptoms are present. National Institute for Health and Professional Excellence has published guidelines on which basis health practitioners may identify patients with a high CRC probability. Suspected CRC recognition and referral for future diagnosis are related to the occurrence of rectal bleeding, abdominal mass, abdominal pain, change in bowel habit, unexplained weight loss and iron-deficiency anemia [ 88 ]. However, some non-site-specific symptoms, such as unexplained appetite loss and deep vein thrombosis, should be mentioned. For these symptoms, an assessment for additional symptoms, signs or findings may help clarify which cancer is most likely to be carried out and offer urgent investigation or a suspected cancer pathway referral [ 89 ].

In some research the usefulness of symptoms of detecting CRC has been evaluated. They present single signs or symptoms that have low utility (sensitivity and specificity) for the CRC diagnosis. Moreover, both positive and negative likelihood ratios (PLR and NLR) confirm the presence or lack of symptoms does not significantly modify the probability of CRC detection [ 90 , 91 , 92 ]. Nevertheless, in clinical practice, according to many guidelines, colonoscopy is performed in patients with bowel signs and symptoms suspected of CRC [ 88 ]. However, some studies suggest that co-occurrence of some symptoms may enhance the diagnostic sensitivity and specificity for colorectal cancer. [ 90 , 91 ], e.g., the presence of a palpable abdominal mass on examination and a report of dark red rectal bleeding [ 90 ] or rectal bleeding and weight loss and change in bowel habit [ 92 ].

In the context of CRC treatment, patients who have been diagnosed before they had symptoms of CRC (or these were the first symptoms) and the disease was detected at an early stage have a much better prognosis. For this reason, all alarming symptoms that may suggest CRC should encourage the patient to see a doctor urgently and have colorectal diagnostic tests done [ 93 ].

6. Diagnostic

For individuals suspected of having CRC, primary care physicians should carry out a physical examination of the abdomen and analyze the health history to diagnose. The suspicion of CRC on physical examination and subject examination indicates that the patient is referred to a gastroenterology clinic. During the visit, the doctor should consult patients in terms of family history, consider assessing risk factors, and then choose an appropriate optical and/or imaging diagnosis method. Another pathway for detecting CRC is various screening programs (pilot, opportunistic or organized) placed worldwide [ 94 ]. Despite a higher number of programs, the participation ranged from 16.1% to 68.2% [ 95 ]. The programs mostly include individuals aged 50–75 years with wide variations in screening practices depending on the protocols resulting from the study stage, colonoscopy capacities and financial resources. Screening programs are implemented more frequently in Western countries with higher CRC prevalence with a different type of test. Most of screening diagnostic methods include fecal immunochemical test for hemoglobin (FIT), guaiac fecal occult blood test (gFOBT), (optical) colonoscopy (OC), flexible sigmoidoscopy (FS) and digital rectal exam (DRE) [ 94 ].

Assessment of family history of cancer in first (FDR), second (SDR) and third-degree relatives is essential to obtain detailed information in the diagnosis process [ 96 ]. Taken information should include relative consanguinity, age at cancer diagnosis, current age or age and cause of death, type of cancer, its medical case history and ethnicity. Research provides that the risk of CRC is the highest, along with patients with FDRs with CRC [ 96 ]. Additionally, the number and degree of relatives determine the screening pathway for CRC diagnosis. In case of one FDR with CRC or more than one FDRs with advanced adenoma was reported, the patient is examined by colonoscopy every 5–10 years or FIT every 1–2 year begins at the age of 40–50 years or 10 years earlier than FDR age of diagnosis. In case of more than one FDRs or SDRs with CRC or polyps and more than two FDRs with CRC is reported in the patients’ family history, the colonoscopy should be done every 5 years beginning at the age of 40 or 10 years earlier than the age of FDR diagnosis [ 97 ]. Other information should include potential determinants such as non-paternity or born resulting from sperm/egg donors. Suppose suspected CRC, syndromes and other syndrome-specific features are diagnosed in personal or family history (e.g., Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis and hamartomatous polyposis syndromes). In that case, the patient should follow high-risk guidelines, and the surveillance should be started by age 20–25 [ 98 , 99 ]. Additionally, in any patient with suspected colorectal cancer, it is recommended to pay attention to peripheral lymphadenopathy, hepatomegaly, a palpable abdominal tumor and the presence of ascites.

The fecal occult blood test is the first-choice screening test in primary care. However, it has been recommended for their implementation to refer patients with low-risk bowel symptoms but has not been recommended for all symptomatic patients [ 88 ]. For CRC screening and detection of occult bleeding, high-sensitivity, guaiac-based (HSgFOBT) or immunochemical-based (FIT) tests are recommended [ 99 ]. gFOBT is not specific to human hemoglobin, and some foods or drugs can affect the results of this test; therefore, it requires some restriction to comply before tested [ 98 ]. FIT measures the amount of human-specific hemoglobin in a feces sample and is recommended in place of gFOBT for patients with low-risk CRC symptoms. NICE guidelines recommend it for the patient with unexplained changes in bowel habits and iron deficiency anemia (patients aged 60 and over, even in the absence of iron deficiency) for use in primary care or screening for suspected CRC [ 88 ]. FIT may help effectively excluded CRC among symptomatic patients [ 100 ] and, in conjunction with clinical assessment, may safely and objectively determine individual risk of CRC for further decisions about urgent or routine management [ 101 ]. Moreover, FIT is preferable to the gFOBT in terms of the detection rate, positive predictive value and participation rate [ 102 ]. Recent meta-analyses confirm that quantitative FIT is highly sensitive for CRC detection [ 103 ] and indicated that at a cut-off around 10 μg Hb/g faces has the potential to rule out CRC correctly and decrease colonoscopy rate in 75–80% of symptomatic patients [ 104 ]. Recommendation to routinely perform FIT in primary care in individuals with unexplained symptoms but no rectal bleeding who do not meet criteria for suspected CRC is currently not sufficiently evidenced [ 88 ]. However, recent research indicates that FIT performs exceptionally well to triage patients with low-risk CRC symptoms [ 105 ].

Endoscopy (colonoscopy, sigmoidoscopy and rectoscope) is the basis for a diagnosis of CRC. It allows tumors to be detected, samples to be taken, and the rest of the bowel to be inspected. Flexible sigmoidoscopy allows visualization of the left-side colon and, if necessary and possible, remove polyps. It does not require thorough patient preparation for the examination as colonoscopy and can be performed by physicians and non-physicians [ 98 ]. Diagnosis by colonoscopy is the procedure with the highest sensitivity and specificity for the diagnosis of colorectal cancer. Colonoscopy makes it possible to assess the entire large intestine and the terminal part of the small intestine. During the examination, it is possible to take a biopsy and then have the material evaluated histopathologically [ 106 ]. High-quality baseline colonoscopy has to meet adequate bowel preparation criteria, complete examination to the cecum, attention to complete polyp excision and performed by a colonoscopist with acceptable adenoma detection rate [ 107 ]. Further scheduling of surveillance colonoscopies depends on the results of the number and size of polyps and adenomas detected during baseline colonoscopy [ 107 ]. New methods such as artificial intelligence are implemented in colonoscopy to support and improve its effectiveness in detecting and assessing colorectal polyps. A computer-aided diagnostic system (CAD) that uses deep-learning technology can accurately determine polyp histology (from 63.8–71.8% to 82.7–84.2%) and may facilitate endoscopist diagnosis [ 108 ]. Additionally, results of deep neural network demonstrated better polyps detection with using narrow-band imaging than white light endoscopy (WLE) (accuracy 95% vs. 74%) and using the two-channel red plus green images than full-color WLE images (74% vs.91%) [ 109 ].

As invasive endoscopy tools are the ideal methods for detecting cancer at an earlier curable stage and removing the precancerous adenomas, some non-invasive methods are accessible to the whole visualization colon with good sensitivity and specificity; however, it does not allow biopsy during imaging. Colon capsule endoscopy (CCE) can be used as an alternative to colonoscopy in screening patients at moderate CRC risk when conventional colonoscopy cannot be performed or is contraindicated or rejected by patients. First-generation CCE has low-quality evidence that would deceive a good sensitivity and specificity for detecting CRC polyps and has a good safety profile [ 110 ]. However, the sensitivity in the detection of polyps >6 mm and >10 mm increased substantially between the development of its first-generation and second-generation [ 111 ], which has a wider angle of view and an adaptive frame rate dependent on the speed of passage of the capsule into the colon [ 112 ]. Despite CEE having a good accuracy in detecting polyps and colorectal cancer among high- and middle-risk patients [ 113 ], it is not recommended as a first-line screening or diagnostic method for CRC [ 114 ].

Computed tomographic colonography (CTC) is a non-invasive, rapid radiographic imagining test. The patient’s preparation for the examination is the same as for colonoscopy, and the examination itself is not very pleasant due to the discomfort caused by the insufflation procedure [ 106 ]. High-quality evidence supports its strong recommendation as an acceptable and equally sensitive radiological examination alternative for the CRC diagnosis for patients with and without alarm symptoms [ 111 ]. This method’s overall sensitivity is comparable to that of colonoscopy but is significantly lower for detecting polyps <8 mm [ 106 ].

Routine imaging-based diagnosis often limits the detection of cancer due to its small size or difficulty in separating it from soft tissues, which is particularly important for diagnosing metastases and assessing response to treatment [ 115 ]. A clinical challenge important for selecting and planning an appropriate management and treatment strategy is to perform a comprehensive clinical analysis that includes the use of the most recent imaging techniques combined with the assessment of tumor biomarkers and genetic features of the tumor [ 115 ]. The detection level of most conventional imagining techniques is insufficient to detect metastases. New techniques such as diffusion-weighted MRI (DW-MRI) or fibroblast activation protein inhibitor–positron emission tomography (FAPI-PET) is prospective due to high specificity and sensitivity, also in the case of extraperitoneal lesions [ 115 , 116 , 117 , 118 ].

An important marker that was supposed to help detect or predict the stadium of CRC is the carcinoembryonic antigen (CEA) concentration. A study in patients with abdominal symptoms, who have been ruled out after a complete colonoscopy, provides that CEA should not be considered to assist in the triage of patients with CRC [ 119 ]. The correlation between CEA levels and level of the tumor differentiation, diameter and staging is weak. In the majority of patients with and without colorectal cancer CEA levels may be within normal limits. Therefore, on this basis, it would not be ruled out the colorectal cancer diagnosis, and these patients should be investigated in detail [ 120 ]. Additionally, the preoperative serum level cannot indicate the specific stage and histopathological size of the CRC [ 121 ]. However, the CEA seems to be of substantial importance as a predictive and prognostic marker of relevance for choosing targeted therapy and for overall and progression-free survival in some types of CRC [ 122 , 123 , 124 ].

Once CRC is confirmed by histopathological examination, further diagnosis is determined individually depending on its findings. Additional diagnostics include imaging studies to assess the local stage, the presence of enlarged lymph nodes and distant metastases and the risk of obstruction. Additionally, based on the presence or absence of specific genetic biomarkers, individualized chemotherapy can be introduced, the efficacy of which may be higher compared to a standard procedure. In colon and rectal cancer appropriate for resection (non-metastatic), chest, abdominal, pelvic computed tomography (CT), pelvic magnetic resonance imagining (MRI), complete blood count, chemistry profile and CEA, enterostomal therapist as indicated for the preoperative marking of the site [ 125 ] and in rectal cancer proctoscopy endorectal ultrasound (if MRI is contraindicated or for superficial lesions) have to be considered [ 99 ]. In both colon and rectal cancer, the positron emission tomography-computed tomography (PET-CT) scan is not indicated, and in appropriate patients, fertility risk should be discussed [ 99 , 126 ]. In case of suspicion or proven metastatic synchronous adenocarcinoma (any T or N, and M1) the diagnosis should be extended by determination of tumor gene status for KRAS and B-RAF mutation and/or HER2 amplifications, testing microsatellite instability (MSI) and mismatch repair (MMR) and consider PET-CT scan (skull base to mid-thigh) and MRI od liver [ 99 , 125 ].

KRAS and BRAF encode a small G protein and a Ser/Thr protein kinase. They take part in regulating the mitogenic signaling cascade of the RAS/RAF/mitogenic-activated protein kinase (MAPK) or PI3K (phosphatidylinositol 3-kinase) pathways, which are activated by the epidermal growth factor receptor (EGFR). EGFR is responsible for stimulates critical processes involved in tumor growth and progression, including proliferation, angiogenesis, invasion and metastasis [ 127 ]. Mutations in the KRAS and B-RAF genes lead to hence constitutive activation of RAS/RAF proteins despite EGFR activation is blocked, and are considered to be an early event in CRC carcinogenesis with presence in about 20–50% cases [ 127 , 128 ]. A polymorphic tandem repeats of short nucleotide sequences distributed through the genome are microsatellites. These sequences are particularly prone to mutation due to polymerase errors, leading to frameshifts and base-pair substitutions during replication of DNA, resulting in shortening or extension of microsatellite regions in neoplastic cells. Mutation or silencing of MMR genes (such as MSH2, MSH6, PMS2 and MLH1) may cause MSI [ 129 , 130 , 131 ]. Patients with advanced CRC lacking KRAS or B-RAF mutations will prefer anti-EGFR therapy. In contrast, standard therapy based on 5-fluorouracil (5-FU) will be predisposed by testing for the presence or absence of chromosome deletions 18q and determining the tumor phenotype based on microsatellite instability (MSI) or microsatellite stability (MSS) [ 128 , 129 , 130 ].

In recent years, researchers have been working extensively to identify new biomarkers for the non-invasive diagnosis of CRC. Still, they currently may be considered as universal one about to predict the risk of invasion, metastasis occurrence or resistance to specific therapeutic regimens [ 132 ] and can be successfully translated into clinical practice [ 133 ]. There are a vast number of candidates for diagnostic biomarkers, depending on their types.

Abnormally methylated genes may affect the function of DNA repair (MGMT), apoptosis (BNIP3, DAPK and PCDH10), cell migration (vimentin and TIMP3), proliferation (CDKN2A, IGF2, MYOD1, RARβ2, SFRP1 and SFRP2), and differentiation (NDRG4), transcriptional regulation (GATA4 and TFAP2E) and others, and support prediction of clinical outcomes, such as treatment and survival prognosis, metastasis occurrence and therapy-resistant [ 134 , 135 ].

Protein biomarkers allow detecting CRC (MST1, serpin family, SEPT 9, leucine-rich alpha-2-glycoprotein 1, EGFR and inter-alpha-trypsin inhibitor heavy-chain family member 4) [ 133 , 136 ], staging existing cancer [ 137 ] and predict response for specific treatment (pEGFR for cetuximab response and PCBP1 and Cdk5 for oxaliplatin resistance) [ 133 ].

Detection of tumor circulating DNA (ctDNA) from dead cancer cells in body fluids may be applied to diagnosis, determine cancer type and grade, prognosis reoccurrence and treatment response [ 138 ]. Liquid biopsies like ctDNA are useful in detecting local tumors and distant metastatic, their types and non-invasive procedure [ 138 , 139 ]. However, these examinations are much adequate for high mutational burden tumors and associated with high false-positive/negative results [ 139 ]. The recent systematic review indicates that epigenetic ctDNA markers are potentially the most promising blood-based assay for CRC detection [ 140 ], and a high sensitivity and specificity screening test ctDNA SEPT9 methylation was approved to use. It is superior to CEA and FIT tests in asymptomatic population screening [ 141 ] and may be effectively used to exclude normal subjects [ 142 ].

MicroRNAs (miRNAs) are non-coding, endogenous, single-stranded RNA of 18–25 nucleotides length and can adversely regulate gene expression in the mechanism promoting the inhibition at the translation level or leading to the degradation of target mRNAs [ 143 ]. Differential expressions of various exosomal miRNAs, both alone and in panels, may constitute a potential biomarker for CRC diagnosis, making possible earlier diagnoses and a more personalized approach. Their role in clinical practice can be associated with diagnostic (miR-329, miR-181a, miR-199b, miR-382, miR-215 and miR-21), also in the early-stage (miR-125a-3p, miR-320c and miRNA-486-5p), prognostic (miR-181a-5p, miR-18a-5p and miR-18b-5p), tumor growth (miR-21, miR-23a, miR-92a and miR-1246) or predictive risk for high risk adenomas to transform in CRC (miR-21, miR-29a, miR-92a and miR-135b) and prognosis place of metastasis (miR-548c-5p and miR-328), predictive for adjuvant treatment and recurrence (miR-4772-3p) or stratification for chemotherapy (miR-21) [ 144 ]. Circulating miRNAs as novel biomarkers remain several challenges to be overcome before their clinical application. A further investigation regarding the origin and biological function of miRNAs is needed. Additionally, an explanation of the mechanisms through which miRNAs might be involved in the resistance to chemotherapy and other targeted therapies is required [ 145 ].

There has been an increased attempt to clarify the relationships between gut microbiota and colorectal cancer. Research results indicate that assessing different microbiota-related biomarkers may be a helpful non-invasive tool in CRC preventing, diagnosing and even treating. Some reviews and meta-analyses reported that specific species and gut bacterial dysbiosis might be related to CRC occurrence and observed in CRC patients and animal models [ 146 ]. As mentioned above, gut dysbiosis with high pathogenic microbiota metabolic activity may lead to deconjugation of bile acids and an increase in the level of secondary bile acids, e.g., deoxycholic acid, with an exert carcinogenic activity. Additionally, procarcinogenic and enterotoxin metabolites, such as sulfides, ammonia, phenols and nitrosamines, produced on the path of bacterial protein fermentation, amino acids degradation or reduction of dietary sulfate might be involved in CRC development [ 146 ]. In addition, gut microbes’ metabolic products may trigger inflammation response, produce reactive oxygen species, toxins or mediators (such as tumor necrosis factor alfa, interleukin-6 and cytokines), which may cause DNA damage and induced dysfunction or damage to epithelial cells [ 58 ]. High prevalence of Fusobacterium nucleatum [ 147 ], Parvimonas micra ATCC 33270, Streptococcus anginosus , Parabacteroides distasonis and other members of Proteobacteria were detected in samples of CRC and adenomas patients and present high discriminatory capacity in diagnosis [ 148 ]. In turn, bacterial as F. nucleatum [ 149 , 150 , 151 ] and Bacteroides fragilis were related with worse prognosis, while Faecalibacterium prausnitzii were common in the survival group [ 150 ]. A fascinating insight is that in F. nucleatum and B. fragilis high abundance group, KRAS and BRAF expression were more noticeable [ 150 ]. Recent work has suggested that fecal microbial composition and metabolites can module the response to chemotherapy or immunotherapy [ 152 ]. These opportunities might be related to stem cell transplantation’s effectiveness and modulating response to immunotherapy and treatment with immune checkpoint inhibitors. Microbial manipulation in the clinical setting by administrating targeted design probiotics may reduce proinflammatory and anti-inflammatory cytokines and locally alter immunity that positively impacts cancer therapies results [ 152 ]. Promising results are presented in the work of Poore et al. [ 153 ], in which using blood microbial DNA allows high cancer type discrimination between cancer and healthy patients. Assessment of microbial blood-based DNA in patients’ plasma, soon, may become a tool with a great potential for scheduling adequate treatment and expected therapeutic response [ 139 ]. However, there is insufficient evidence to recommend a microbiome-based test in place currently-used FIT or gFOBT as a non-invasive and inexpensive diagnostic tool in population-based screening programs [ 154 ]. Due to wide variability in bacterial species that may cause CRC, experts representing various fields need to collaborate to develop an inhibition strategy before progression to the neoplastic stage.

7. Conclusions

Further clinical studies are needed to understand the mechanisms of carcinogenesis, the impact of lifestyle, behavioral, environmental and genetic factors, or the synergistic action of the different aspects to increase preventive/treatment efficacy and patient survival with CRC.

Moreover, researchers are still searching for new tumor markers useful for diagnosis in primary and secondary care, but despite promising results, the evidence to date is insufficient. The ongoing research is critical to developing future strategies to control the burden of this disease through population-based prevention initiatives and demonstrates areas for further improvements in multidisciplinary cooperation.

Author Contributions

Conceptualization, T.S.; writing—original draft preparation, T.S., M.R., A.D., E.N., T.A., K.E.P.; writing—review and editing, T.S., M.R., A.D.; visualization, T.S., M.R., T.A.; supervision, T.A., K.E.P. All authors have read and agreed to the published version of the manuscript.

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

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