Globally, colorectal cancer (CRC) is the third most commonly diagnosed malignancy and the second leading cause of cancer death. Arising through three major pathways, including adenoma–carcinoma sequence, serrated pathway and inflammatory pathway, CRC represents an aetiologically heterogeneous disease according to subtyping by tumour anatomical location or global molecular alterations. Genetic factors such as germline MLH1 and APC mutations have an aetiologic role, predisposing individuals to CRC. Yet, the majority of CRC is sporadic and largely attributable to the constellation of modifiable environmental risk factors characterizing westernization (for example, obesity, physical inactivity, poor diets, alcohol drinking and smoking). As such, the burden of CRC is shifting towards low-income and middle-income countries as they become westernized. Furthermore, the rising incidence of CRC at younger ages (before age 50 years) is an emerging trend. This Review provides a comprehensive summary of CRC epidemiology, with emphasis on modifiable lifestyle and nutritional factors, chemoprevention and screening. Overall, the optimal reduction of CRC incidence and mortality will require concerted efforts to reduce modifiable risk factors, to leverage chemoprevention research and to promote population-wide and targeted screening.
Certain global genetic and epigenetic aberrations are disproportionally distributed across the colorectum, which corresponds to aetiological heterogeneity of colorectal cancer (CRC), especially hypermutated cancers, by anatomical location
With increasing incidence of CRC at younger ages, there is an urgent need to better identify high-risk individuals younger than 50 years, the age when screening typically starts
The constellation of factors associated with westernization, such as obesity, physical inactivity, poor diets, alcohol drinking and smoking, is likely to drive increasing CRC incidence in economically transitioning countries
Evidence indicates that aspirin probably confers chemopreventive benefit against CRC, though recommendation for its widespread prophylactic use is currently premature
Screening colonoscopy and faecal occult blood test, when implemented appropriately per national financial and medical resources and CRC incidence, could contribute to secondary prevention of CRC
The optimal reduction of CRC incidence and mortality will require concerted efforts to reduce modifiable risk factors, to leverage chemoprevention research and to promote population-wide and targeted screening
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Application of nanotechnology in the early diagnosis and comprehensive treatment of gastrointestinal cancer
Journal of Nanobiotechnology Open Access 15 September 2022
Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer
Cancer Cell International Open Access 11 August 2022
The clinicopathological and prognostic significances of IGF-1R and Livin expression in patients with colorectal cancer
BMC Cancer Open Access 05 August 2022
Subscribe to Nature+
Get immediate online access to the entire Nature family of 50+ journals
Subscribe to Journal
Get full journal access for 1 year
only $8.25 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Get time limited or full article access on ReadCube.
All prices are NET prices.
Fleming, M., Ravula, S., Tatishchev, S. F. & Wang, H. L. Colorectal carcinoma: pathologic aspects. J. Gastrointest. Oncol. 3, 153–173 (2012).
Jasperson, K. W., Tuohy, T. M., Neklason, D. W. & Burt, R. W. Hereditary and familial colon cancer. Gastroenterology 138, 2044–2058 (2010).
Graff, R. E. et al. Familial risk and heritability of colorectal cancer in the nordic twin study of cancer. Clin. Gastroenterol. Hepatol. 15, 1256–1264 (2017).
Lichtenstein, P. et al. Environmental and heritable factors in the causation of cancer—analyses of cohorts of twins from Sweden, Denmark, and Finland. N. Engl. J Med. 343, 78–85 (2000).
Jiao, S. et al. Estimating the heritability of colorectal cancer. Hum. Mol. Genet. 23, 3898–3905 (2014).
International Agency for Research on Cancer. Globocan 2018: Cancer Fact Sheets — Colorectal Cancer. IARC http://gco.iarc.fr/today/data/factsheets/cancers/10_8_9-Colorectum-fact-sheet.pdf (2018).
Brenner, H., Stock, C. & Hoffmeister, M. Effect of screening sigmoidoscopy and screening colonoscopy on colorectal cancer incidence and mortality: systematic review and meta-analysis of randomised controlled trials and observational studies. BMJ 348, g2467 (2014).
Schreuders, E. H. et al. Colorectal cancer screening: a global overview of existing programmes. Gut 64, 1637–1649 (2015).
World Cancer Research Fund International/American Institute for Cancer Research. Continuous update project report: Diet, nutrition, physical activity, and colorectal cancer. American Institute for Cancer Research https://www.aicr.org/continuous-update-project/reports/colorectal-cancer-2017-report.pdf (2018).
Center, M. M., Jemal, A. & Ward, E. International trends in colorectal cancer incidence rates. Cancer Epidemiol. Biomarkers Prev. 18, 1688–1694 (2009).
United Nations Development Programme. 2018 Statistical Update and Human Development Index. United Nations Development Programme http://hdr.undp.org/ (2018).
Arnold, M. et al. Global patterns and trends in colorectal cancer incidence and mortality. Gut 66, 683–691 (2017).
Imamura, F. et al. Dietary quality among men and women in 187 countries in 1990 and 2010: a systematic assessment. Lancet Glob. Health 3, e132–e142 (2015).
World Health Organization. Mean Body Mass Index Trends Among Adults, Age-Standardized Estimates by Country. World Health Organization http://apps.who.int/gho/data/node.main.A904?lang=en (2017).
Mousavi, S. M., Fallah, M., Sundquist, K. & Hemminki, K. Age- and time-dependent changes in cancer incidence among immigrants to Sweden: colorectal, lung, breast and prostate cancers. Int. J. Cancer 131, E122–E128 (2012).
Karastergiou, K., Smith, S. R., Greenberg, A. S. & Fried, S. K. Sex differences in human adipose tissues – the biology of pear shape. Biol. Sex Differ. 3, 13 (2012).
Wilsnack, R. W., Wilsnack, S. C., Kristjanson, A. F., Vogeltanz-Holm, N. D. & Gmel, G. Gender and alcohol consumption: patterns from the multinational GENACIS project. Addiction 104, 1487–1500 (2009).
World Health Organization. WHO Global Report on Trends in Prevalence of Tobacco Smoking. 2015. World Health Organization http://apps.who.int/iris/bitstream/handle/10665/156262/9789241564922_eng.pdf;jsessionid=3E603A72D553D128773D0836AECE325E?sequence=1 (2015).
Clarke, N., Sharp, L., Osborne, A. & Kearney, P. M. Comparison of uptake of colorectal cancer screening based on fecal immunochemical testing (FIT) in males and females: a systematic review and meta-analysis. Cancer Epidemiol. Biomarkers Prev. 24, 39–47 (2015).
Murphy, N. et al. A prospective evaluation of endogenous sex hormone levels and colorectal cancer risk in postmenopausal women. J. Natl Cancer. Inst. 107, djv210 (2015).
U.S. Cancer Statistics Working Group. U.S. Cancer Statistics Data Visualizations Tool, based on November 2017 submission data (1999-2015): U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute. Centers for Disease Control and Prevention www.cdc.gov/cancer/dataviz (2016).
Augustus, G. J. & Ellis, N. A. Colorectal cancer disparity in african americans: risk factors and carcinogenic mechanisms. Am. J. Pathol. 188, 291–303 (2018).
Ashktorab, H. et al. Identification of novel mutations by exome sequencing in African American colorectal cancer patients. Cancer 121, 34–42 (2015).
Wang, H. et al. Novel colon cancer susceptibility variants identified from a genome-wide association study in African Americans. Int. J. Cancer 140, 2728–2733 (2017).
Huyghe, J. R. et al. Discovery of common and rare genetic risk variants for colorectal cancer. Nat. Genet. 51, 76–87 (2019).
Ashktorab, H. et al. A meta-analysis of MSI frequency and race in colorectal cancer. Oncotarget 7, 34546–34557 (2016).
Pawlik, T. M., Raut, C. P. & Rodriguez-Bigas, M. A. Colorectal carcinogenesis: MSI-H versus MSI-L. Dis. Markers 20, 199–206 (2004).
Guindalini, R. S. et al. Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. Gastroenterology 149, 1446–1453 (2015).
Pitot, H. C. The molecular biology of carcinogenesis. Cancer 72, 962–970 (1993).
Carethers, J. M. & Jung, B. H. Genetics and genetic biomarkers in sporadic colorectal cancer. Gastroenterology 149, 1177–1190.e3 (2015).
Munro, M. J., Wickremesekera, S. K., Peng, L., Tan, S. T. & Itinteang, T. Cancer stem cells in colorectal cancer: a review. J. Clin. Pathol. 71, 110–116 (2018).
Ogino, S. & Goel, A. Molecular classification and correlates in colorectal cancer. J. Mol. Diagn. 10, 13–27 (2008).
Grady, W. M. & Carethers, J. M. Genomic and epigenetic instability in colorectal cancer pathogenesis. Gastroenterology 135, 1079–1099 (2008).
Bakhoum, S. F. et al. The mitotic origin of chromosomal instability. Curr. Biol. 24, R148–R149 (2014).
Nazemalhosseini Mojarad, E., Kuppen, P. J., Aghdaei, H. A. & Zali, M. R. The CpG island methylator phenotype (CIMP) in colorectal cancer. Gastroenterol. Hepatol. Bed Bench 6, 120–128 (2013).
Markowitz, S. D. & Bertagnolli, M. M. Molecular origins of cancer: molecular basis of colorectal cancer. N. Engl J. Med. 361, 2449–2460 (2009).
Jia, M., Gao, X., Zhang, Y., Hoffmeister, M. & Brenner, H. Different definitions of CpG island methylator phenotype and outcomes of colorectal cancer: a systematic review. Clin. Epigenetics 8, 25 (2016).
Funkhouser, W. K. Jr. et al. Relevance, pathogenesis, and testing algorithm for mismatch repair-defective colorectal carcinomas: a report of the association for molecular pathology. J. Mol. Diagn. 14, 91–103 (2012).
Weisenberger, D. J. et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat. Genet. 38, 787–793 (2006).
Conteduca, V., Sansonno, D., Russi, S. & Dammacco, F. Precancerous colorectal lesions (Review). Int. J. Oncol. 43, 973–984 (2013).
Winawer, S. J. et al. Colorectal cancer screening: clinical guidelines and rationale. Gastroenterology 112, 594–642 (1997).
Brenner, H. et al. Risk of progression of advanced adenomas to colorectal cancer by age and sex: estimates based on 840,149 screening colonoscopies. Gut 56, 1585–1589 (2007).
Strum, W. B. Colorectal adenomas. N. Engl J. Med. 374, 1065–1075 (2016).
East, J. E. et al. British Society of Gastroenterology position statement on serrated polyps in the colon and rectum. Gut 66, 1181–1196 (2017).
Erichsen, R. et al. Increased risk of colorectal cancer development among patients with serrated polyps. Gastroenterology 150, 895–902e5 (2016).
Dow, L. E. et al. Apc restoration promotes cellular differentiation and reestablishes crypt homeostasis in colorectal cancer. Cell 161, 1539–1552 (2015).
Armaghany, T., Wilson, J. D., Chu, Q. & Mills, G. Genetic alterations in colorectal cancer. Gastrointest. Cancer Res. 5, 19–27 (2012).
Pino, M. S. & Chung, D. C. The chromosomal instability pathway in colon cancer. Gastroenterology 138, 2059–2072 (2010).
Leggett, B. & Whitehall, V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 138, 2088–2100 (2010).
Kedrin, D. & Gala, M. K. Genetics of the serrated pathway to colorectal cancer. Clin. Transl Gastroenterol. 6, e84 (2015).
O’Brien, M. J. et al. Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am. J. Surg. Pathol. 30, 1491–1501 (2006).
Kim, K. M. et al. Molecular features of colorectal hyperplastic polyps and sessile serrated adenoma/polyps from Korea. Am. J. Surg. Pathol. 35, 1274–1286 (2011).
Yang, S., Farraye, F. A., Mack, C., Posnik, O. & O’Brien, M. J. BRAF and KRAS mutations in hyperplastic polyps and serrated adenomas of the colorectum: relationship to histology and CpG island methylation status. Am. J. Surg. Pathol. 28, 1452–1459 (2004).
Jess, T., Rungoe, C. & Peyrin-Biroulet, L. Risk of colorectal cancer in patients with ulcerative colitis: a meta-analysis of population-based cohort studies. Clin. Gastroenterol. Hepatol. 10, 639–645 (2012).
Itzkowitz, S. H. & Yio, X. Inflammation and cancer IV. Colorectal cancer in inflammatory bowel disease: the role of inflammation. Am. J. Physiol. Gastrointest. Liver Physiol. 287, G7–G17 (2004).
Buchner, A. M. & Lichtenstein, G. R. Evaluation and detection of dysplasia in IBD: the role of chromoendoscopy and enhanced imaging techniques. Curr. Treat. Options Gastroenterol. 14, 73–82 (2016).
Robles, A. I. et al. Whole-exome sequencing analyses of inflammatory bowel disease-associated colorectal cancers. Gastroenterology 150, 931–943 (2016).
Triantafillidis, J. K., Nasioulas, G. & Kosmidis, P. A. Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. Anticancer Res. 29, 2727–2737 (2009).
Li, F. Y. & Lai, M. D. Colorectal cancer, one entity or three. J. Zhejiang Univ. Sci. B 10, 219–229 (2009).
Murphy, N. et al. Heterogeneity of colorectal cancer risk factors by anatomical subsite in 10 European countries: a multinational cohort study. Clin. Gastroenterol. Hepatol. 17, 1323–1331.e6 (2019).
Wei, E. K. et al. Comparison of risk factors for colon and rectal cancer. Int. J. Cancer 108, 433–442 (2004).
Drewes, J. L., Housseau, F. & Sears, C. L. Sporadic colorectal cancer: microbial contributors to disease prevention, development and therapy. Br. J. Cancer 115, 273–280 (2016).
Yang, L. et al. Proximal shift of colorectal cancer with increasing age in different ethnicities. Cancer Manag. Res. 10, 2663–2673 (2018).
Murphy, G. et al. Sex disparities in colorectal cancer incidence by anatomic subsite, race and age. Int. J. Cancer 128, 1668–1675 (2011).
Shin, A. et al. Increasing trend of colorectal cancer incidence in Korea, 1999-2009. Cancer Res. Treat. 44, 219–226 (2012).
Missiaglia, E. et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Ann. Oncol. 25, 1995–2001 (2014).
Cancer Genome Atlas Network. Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337 (2012).
Guastadisegni, C., Colafranceschi, M., Ottini, L. & Dogliotti, E. Microsatellite instability as a marker of prognosis and response to therapy: a meta-analysis of colorectal cancer survival data. Eur. J. Cancer 46, 2788–2798 (2010).
Boland, C. R. & Goel, A. Microsatellite instability in colorectal cancer. Gastroenterology 138, 2073–2087.e3 (2010).
Schumacher, T. N. & Schreiber, R. D. Neoantigens in cancer immunotherapy. Science 348, 69–74 (2015).
Westdorp, H. et al. Opportunities for immunotherapy in microsatellite instable colorectal cancer. Cancer Immunol. Immunother. 65, 1249–1259 (2016).
Giannakis, M. et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15, 857–865 (2016).
Passardi, A., Canale, M., Valgiusti, M. & Ulivi, P. Immune checkpoints as a target for colorectal cancer treatment. Int. J. Mol. Sci. 18, E1324 (2017).
Jia, M. et al. No association of CpG island methylator phenotype and colorectal cancer survival: population-based study. Br. J. Cancer 115, 1359–1366 (2016).
Jass, J. R. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 50, 113–130 (2007).
Guinney, J. et al. The consensus molecular subtypes of colorectal cancer. Nat. Med. 21, 1350–1356 (2015).
Alwers, E. et al. Associations between molecular classifications of colorectal cancer and patient survival: a systematic review. Clin. Gastroenterol. Hepatol. 17, 402–410.e2 (2019).
Butterworth, A. S., Higgins, J. P. & Pharoah, P. Relative and absolute risk of colorectal cancer for individuals with a family history: a meta-analysis. Eur. J. Cancer 42, 216–227 (2006).
Weigl, K. et al. Strongly enhanced colorectal cancer risk stratification by combining family history and genetic risk score. Clin. Epidemiol. 10, 143–152 (2018).
Rahner, N. & Steinke, V. Hereditary cancer syndromes. Dtsch. Arztebl. Int. 105, 706–714 (2008).
Mork, M. E. et al. High prevalence of hereditary cancer syndromes in adolescents and young adults with colorectal cancer. J. Clin. Oncol. 33, 3544–3549 (2015).
Goodenberger, M. L. et al. PMS2 monoallelic mutation carriers: the known unknown. Genet. Med. 18, 13–19 (2016).
Win, A. K. et al. Prevalence and penetrance of major genes and polygenes for colorectal cancer. Cancer Epidemiol. Biomarkers Prev. 26, 404–412 (2017).
Lynch, H. T. & de la Chapelle, A. Hereditary colorectal cancer. N. Engl. J. Med. 348, 919–932 (2003).
Lindgren, G., Liljegren, A., Jaramillo, E., Rubio, C. & Lindblom, A. Adenoma prevalence and cancer risk in familial non-polyposis colorectal cancer. Gut 50, 228–234 (2002).
Jass, J. R. et al. Pathology of hereditary non-polyposis colorectal cancer. Anticancer Res. 14, 1631–1634 (1994).
Half, E., Bercovich, D. & Rozen, P. Familial adenomatous polyposis. Orphanet J. Rare Dis. 4, 22 (2009).
Patel, S. G. & Ahnen, D. J. Familial colon cancer syndromes: an update of a rapidly evolving field. Curr. Gastroenterol. Rep. 14, 428–438 (2012).
Murphy, C. C. & Singal, A. G. Establishing a research agenda for early-onset colorectal cancer. PLOS Med. 15, e1002577 (2018).
Pearlman, R. et al. Prevalence and spectrum of germline cancer susceptibility gene mutations among patients with early-onset colorectal cancer. JAMA Oncol. 3, 464–471 (2017).
Crosbie, A. B. et al. Trends in colorectal cancer incidence among younger adults-disparities by age, sex, race, ethnicity, and subsite. Cancer Med. 7, 4077–4086 (2018).
Ballester, V., Rashtak, S. & Boardman, L. Clinical and molecular features of young-onset colorectal cancer. World J. Gastroenterol. 22, 1736–1744 (2016).
Kim, T. J., Kim, E. R., Hong, S. N., Chang, D. K. & Kim, Y. H. Long-term outcome and prognostic factors of sporadic colorectal cancer in young patients: a large institutional-based retrospective study. Medicine 95, e3641 (2016).
Nimptsch, K. & Wu, K. Is timing important? the role of diet and lifestyle during early life on colorectal neoplasia. Curr. Colorectal Cancer Rep. 14, 1–11 (2018).
NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults. Lancet 390, 2627–2642 (2017).
Liu, P. H. et al. Association of obesity with risk of early-onset colorectal cancer among women. JAMA Oncol. 5, 37–44 (2019).
Renehan, A. G., Tyson, M., Egger, M., Heller, R. F. & Zwahlen, M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 371, 569–578 (2008).
Dong, Y. et al. Abdominal obesity and colorectal cancer risk: systematic review and meta-analysis of prospective studies. Biosci. Rep. 37, BSR20170945 (2017).
Kune, G. A. The Melbourne Colorectal Cancer Study: reflections on a 30-year experience. Med. J. Aust. 193, 648–652 (2010).
Mansournia, M. A. & Altman, D. G. Population attributable fraction. BMJ 360, k757 (2018).
Liang, P. S., Chen, T. Y. & Giovannucci, E. Cigarette smoking and colorectal cancer incidence and mortality: systematic review and meta-analysis. Int. J. Cancer 124, 2406–2415 (2009).
Song, M. et al. Long-term status and change of body fat distribution, and risk of colorectal cancer: a prospective cohort study. Int. J. Epidemiol. 45, 871–883 (2016).
Moore, L. L. et al. BMI and waist circumference as predictors of lifetime colon cancer risk in Framingham Study adults. Int. J. Obes. Relat. Metab. Disord. 28, 559–567 (2004).
Samaras, K., Botelho, N. K., Chisholm, D. J. & Lord, R. V. Subcutaneous and visceral adipose tissue gene expression of serum adipokines that predict type 2 diabetes. Obesity 18, 884–889 (2010).
Bruun, J. M., Lihn, A. S., Pedersen, S. B. & Richelsen, B. Monocyte chemoattractant protein-1 release is higher in visceral than subcutaneous human adipose tissue (AT): implication of macrophages resident in the AT. J. Clin. Endocrinol. Metab. 90, 2282–2289 (2005).
Ouchi, N., Parker, J. L., Lugus, J. J. & Walsh, K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol. 11, 85–97 (2011).
Park, J., Morley, T. S., Kim, M., Clegg, D. J. & Scherer, P. E. Obesity and cancer–mechanisms underlying tumour progression and recurrence. Nat. Rev. Endocrinol. 10, 455–465 (2014).
Calle, E. E. & Kaaks, R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat. Rev. Cancer 4, 579–591 (2004).
Keum, N., Lee, D. H., Kim, R., Greenwood, D. C. & Giovannucci, E. L. Visceral adiposity and colorectal adenomas: dose-response meta-analysis of observational studies. Ann. Oncol. 26, 1101–1109 (2015).
Lim, U. et al. Asian women have greater abdominal and visceral adiposity than Caucasian women with similar body mass index. Nutr. Diabetes 1, e6 (2011).
Wang, T. et al. Effects of obesity related genetic variations on visceral and subcutaneous fat distribution in a chinese population. Sci. Rep. 6, 20691 (2016).
Leeners, B., Geary, N., Tobler, P. N. & Asarian, L. Ovarian hormones and obesity. Hum. Reprod. Update 23, 300–321 (2017).
Ning, Y., Wang, L. & Giovannucci, E. L. A quantitative analysis of body mass index and colorectal cancer: findings from 56 observational studies. Obes. Rev. 11, 19–30 (2010).
Kim, H. & Giovannucci, E. L. Sex differences in the association of obesity and colorectal cancer risk. Cancer Causes Control 28, 1–4 (2017).
Thrift, A. P. et al. Mendelian randomization study of body mass index and colorectal cancer risk. Cancer Epidemiol. Biomarkers Prev. 24, 1024–1031 (2015).
World Cancer Research Fund/American Institute for Cancer Research. World Cancer Research Fund Internationl Systematic Literature Review: The Associations between Food, Nutrition and Physical Activity and the Risk of Colorectal Cancer, 2017. World Cancer Research Fund https://www.wcrf.org/sites/default/files/colorectal-cancer-slr.pdf (2017).
Hetemaki, N. et al. Estrogen metabolism in abdominal subcutaneous and visceral adipose tissue in postmenopausal women. J. Clin. Endocrinol. Metab. 102, 4588–4595 (2017).
Rezende, L. F. M. et al. Physical activity and cancer: an umbrella review of the literature including 22 major anatomical sites and 770 000 cancer cases. Br. J. Sports Med. 52, 826–833 (2018).
Kushi, L. H. et al. American Cancer Society Guidelines on Nutrition and Physical Activity for Cancer Prevention: reducing the risk of cancer with healthy food choices and physical activity. CA Cancer J. Clin. 62, 30–67 (2012).
Ainsworth, B. E. et al. 2011 Compendium of Physical Activities: a second update of codes and MET values. Med. Sci. Sports Exerc. 43, 1575–1581 (2011).
Ruiz-Casado, A. et al. Exercise and the hallmarks of cancer. Trends Cancer 3, 423–441 (2017).
Giovannucci, E. An integrative approach for deciphering the causal associations of physical activity and cancer risk: the role of adiposity. J. Natl Cancer Inst. 110, 935–941 (2018).
Ross, R. et al. Reduction in obesity and related comorbid conditions after diet-induced weight loss or exercise-induced weight loss in men. A randomized, controlled trial. Ann. Intern. Med. 133, 92–103 (2000).
Ross, R. et al. Exercise-induced reduction in obesity and insulin resistance in women: a randomized controlled trial. Obes. Res. 12, 789–798 (2004).
Ismail, I., Keating, S. E., Baker, M. K. & Johnson, N. A. A systematic review and meta-analysis of the effect of aerobic vs. resistance exercise training on visceral fat. Obes. Rev. 13, 68–91 (2012).
Keum, N. et al. Association of physical activity by type and intensity with digestive system cancer risk. JAMA Oncol. 2, 1146–1153 (2016).
Schmid, D. & Leitzmann, M. F. Television viewing and time spent sedentary in relation to cancer risk: a meta-analysis. J. Natl Cancer Inst. 106, dju098 (2014).
Ma, P., Yao, Y., Sun, W., Dai, S. & Zhou, C. Daily sedentary time and its association with risk for colorectal cancer in adults: a dose-response meta-analysis of prospective cohort studies. Medicine 96, e7049 (2017).
Lynch, B. M. Sedentary behavior and cancer: a systematic review of the literature and proposed biological mechanisms. Cancer Epidemiol. Biomarkers Prev. 19, 2691–2709 (2010).
Healy, G. N. et al. Breaks in sedentary time: beneficial associations with metabolic risk. Diabetes Care 31, 661–666 (2008).
Cespedes, E. M. & Hu, F. B. Dietary patterns: from nutritional epidemiologic analysis to national guidelines. Am. J. Clin. Nutr. 101, 899–900 (2015).
Tabung, F. K., Brown, L. S. & Fung, T. T. Dietary patterns and colorectal cancer risk: a review of 17 years of evidence (2000-2016). Curr. Colorectal Cancer Rep. 13, 440–454 (2017).
Garcia-Larsen, V. et al. Dietary patterns derived from principal component analysis (PCA) and risk of colorectal cancer: a systematic review and meta-analysis. Eur. J. Clin. Nutr. 73, 366–386 (2019).
Vieira, A. R. et al. Foods and beverages and colorectal cancer risk: a systematic review and meta-analysis of cohort studies, an update of the evidence of the WCRF-AICR Continuous Update Project. Ann. Oncol. 28, 1788–1802 (2017).
Cascella, M. et al. Dissecting the mechanisms and molecules underlying the potential carcinogenicity of red and processed meat in colorectal cancer (CRC): an overview on the current state of knowledge. Infect. Agent Cancer 13, 3 (2018).
Helmus, D. S., Thompson, C. L., Zelenskiy, S., Tucker, T. C. & Li, L. Red meat-derived heterocyclic amines increase risk of colon cancer: a population-based case-control study. Nutr. Cancer 65, 1141–1150 (2013).
Bastide, N. M., Pierre, F. H. & Corpet, D. E. Heme iron from meat and risk of colorectal cancer: a meta-analysis and a review of the mechanisms involved. Cancer Prev. Res. 4, 177–184 (2011).
Gamage, S. M. K., Dissabandara, L., Lam, A. K. & Gopalan, V. The role of heme iron molecules derived from red and processed meat in the pathogenesis of colorectal carcinoma. Crit. Rev. Oncol. Hematol. 126, 121–128 (2018).
Fung, T. T. et al. A dietary pattern that is associated with C-peptide and risk of colorectal cancer in women. Cancer Causes Control 23, 959–965 (2012).
Tabung, F. K. et al. Association of dietary inflammatory potential with colorectal cancer risk in men and women. JAMA Oncol. 4, 366–373 (2018).
Burkitt, D. P. Epidemiology of cancer of the colon and rectum. Cancer 28, 3–13 (1971).
Holscher, H. D. Dietary fiber and prebiotics and the gastrointestinal microbiota. Gut Microbes 8, 172–184 (2017).
Zeng, H., Lazarova, D. L. & Bordonaro, M. Mechanisms linking dietary fiber, gut microbiota and colon cancer prevention. World J. Gastrointest. Oncol. 6, 41–51 (2014).
Zeng, H., Taussig, D. P., Cheng, W. H., Johnson, L. K. & Hakkak, R. Butyrate inhibits cancerous HCT116 colon cell proliferation but to a lesser extent in noncancerous NCM460 colon cells. Nutrients 9, E25 (2017).
Elce, A. et al. Butyrate modulating effects on pro-inflammatory pathways in human intestinal epithelial cells. Benef. Microbes 8, 841–847 (2017).
Shang, F. M. & Liu, H. L. Fusobacterium nucleatum and colorectal cancer: a review. World J. Gastrointest. Oncol. 10, 71–81 (2018).
Mehta, R. S. et al. Association of dietary patterns with risk of colorectal cancer subtypes classified by fusobacterium nucleatum in tumor tissue. JAMA Oncol. 3, 921–927 (2017).
Aune, D. et al. Dietary fibre, whole grains, and risk of colorectal cancer: systematic review and dose-response meta-analysis of prospective studies. BMJ 343, d6617 (2011).
Kunzmann, A. T. et al. Dietary fiber intake and risk of colorectal cancer and incident and recurrent adenoma in the prostate, lung, colorectal, and ovarian cancer screening trial. Am. J. Clin. Nutr. 102, 881–890 (2015).
Song, M. et al. Fiber intake and survival after colorectal cancer diagnosis. JAMA Oncol. 4, 71–79 (2018).
Alberts, D. S. et al. Lack of effect of a high-fiber cereal supplement on the recurrence of colorectal adenomas. phoenix colon cancer prevention physicians’ network. N. Engl. J. Med. 342, 1156–1162 (2000).
World Cancer Research Fund International/American Institute for Cancer Research. Continuous update project report: Food, nutrition, physical activity, and the prevention of colorectal cancer. World Cancer Research Fund https://www.wcrf.org/sites/default/files/Colorectal-Cancer-2011-Report.pdf (2011).
International Agency for Research on Cancer. Agents Classified by the IARC Monographs, volumes 1-122. International Agency for Research on Cancer https://monographs.iarc.fr/agents-classified-by-the-iarc/ (2018).
Choi, Y. J., Myung, S. K. & Lee, J. H. Light alcohol drinking and risk of cancer: a meta-analysis of cohort studies. Cancer Res. Treat. 50, 474–487 (2018).
Cho, E. et al. Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann. Intern. Med. 140, 603–613 (2004).
Salaspuro, M. Microbial metabolism of ethanol and acetaldehyde and clinical consequences. Addict. Biol. 2, 35–46 (1997).
Seitz, H. K. & Stickel, F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat. Rev. Cancer 7, 599–612 (2007).
Giovannucci, E. Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies. J. Nutr. 134, 2475S–2481S (2004).
Chang, J. S., Hsiao, J. R. & Chen, C. H. ALDH2 polymorphism and alcohol-related cancers in Asians: a public health perspective. J. Biomed. Sci. 24, 19 (2017).
Li, H. et al. Refined geographic distribution of the oriental ALDH2*504Lys (nee 487Lys) variant. Ann. Hum. Genet. 73, 335–345 (2009).
Mizoue, T. et al. Alcohol drinking and colorectal cancer in Japanese: a pooled analysis of results from five cohort studies. Am. J. Epidemiol. 167, 1397–1406 (2008).
Zhao, H., Liu, K. J., Lei, Z. D., Lei, S. L. & Tian, Y. Q. Meta-analysis of the aldehyde dehydrogenases-2 (ALDH2) Glu487Lys polymorphism and colorectal cancer risk. PLOS ONE 9, e88656 (2014).
Giovannucci, E. & Martinez, M. E. Tobacco, colorectal cancer, and adenomas: a review of the evidence. J. Natl Cancer Inst. 88, 1717–1730 (1996).
Johnson, C. M. et al. Meta-analyses of colorectal cancer risk factors. Cancer Causes Control 24, 1207–1222 (2013).
Limsui, D. et al. Cigarette smoking and colorectal cancer risk by molecularly defined subtypes. J. Natl Cancer Inst. 102, 1012–1022 (2010).
Carr, P. R. et al. Lifestyle factors and risk of sporadic colorectal cancer by microsatellite instability status: a systematic review and meta-analyses. Ann. Oncol. 29, 825–834 (2018).
Figueiredo, J. et al. Smoking-association risks of conventional adenomas and serrated polyps in the colorectum. Cancer Causes Control 26, 377–389 (2015).
Zeilinger, S. et al. Tobacco smoking leads to extensive genome-wide changes in DNA methylation. PLOS ONE 8, e63812 (2013).
Nishihara, R. et al. A prospective study of duration of smoking cessation and colorectal cancer risk by epigenetics-related tumor classification. Am. J. Epidemiol. 178, 84–100 (2013).
Bae, J. M., Kim, J. H. & Kang, G. H. Molecular subtypes of colorectal cancer and their clinicopathologic features, with an emphasis on the serrated neoplasia pathway. Arch. Pathol. Lab. Med. 140, 406–412 (2016).
Rogot, E. & Murray, J. L. Smoking and causes of death among U.S. veterans: 16 years of observation. Public Health Rep. 95, 213–222 (1980).
Heineman, E. F., Zahm, S. H., McLaughlin, J. K. & Vaught, J. B. Increased risk of colorectal cancer among smokers: results of a 26-year follow-up of US veterans and a review. Int. J. Cancer 59, 728–738 (1994).
Lin, J. H. et al. Association between sex hormones and colorectal cancer risk in men and women. Clin. Gastroenterol. Hepatol. 11, 419–424.e1 (2013).
Freeman, E. W., Sammel, M. D., Lin, H. & Gracia, C. R. Obesity and reproductive hormone levels in the transition to menopause. Menopause 17, 718–726 (2010).
Kelly, D. M. & Jones, T. H. Testosterone and obesity. Obes. Rev. 16, 581–606 (2015).
Hillman, E. T., Lu, H., Yao, T. & Nakatsu, C. H. Microbial ecology along the gastrointestinal tract. Microbes Environ. 32, 300–313 (2017).
Flemer, B. et al. Tumour-associated and non-tumour-associated microbiota in colorectal cancer. Gut 66, 633–643 (2017).
Zhang, Y. et al. Changes in gut microbiota and plasma inflammatory factors across the stages of colorectal tumorigenesis: a case-control study. BMC Microbiol. 18, 92 (2018).
O’Keefe, S. J. et al. Fat, fibre and cancer risk in African Americans and rural Africans. Nat. Commun. 6, 6342 (2015).
Allen, J. M. et al. Exercise alters gut microbiota composition and function in lean and obese humans. Med. Sci. Sports Exerc. 50, 747–757 (2018).
Louis, S., Tappu, R. M., Damms-Machado, A., Huson, D. H. & Bischoff, S. C. Characterization of the gut microbial community of obese patients following a weight-loss intervention using whole metagenome shotgun sequencing. PLOS ONE 11, e0149564 (2016).
Ley, R. E., Turnbaugh, P. J., Klein, S. & Gordon, J. I. Microbial ecology: human gut microbes associated with obesity. Nature 444, 1022–1023 (2006).
Coker, O. O. et al. Enteric fungal microbiota dysbiosis and ecological alterations in colorectal cancer. Gut 68, 654–662 (2019).
Nakatsu, G. et al. Alterations in enteric virome are associated with colorectal cancer and survival outcomes. Gastroenterology 155, 529–541.e5 (2018).
Rothwell, P. M. et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376, 1741–1750 (2010).
Cook, N. R. et al. Low-dose aspirin in the primary prevention of cancer the women’s health study: a randomized controlled trial. JAMA 294, 47–55 (2005).
Cook, N. R., Lee, I. M., Zhang, S. M. M., Moorthy, M. V. & Buring, J. E. Alternate-day, low-dose aspirin and cancer risk: long-term observational follow-up of a randomized trial. Ann. Int. Med. 159, 77–85 (2013).
Giovannucci, E. et al. Aspirin and the risk of colorectal-cancer in women. N. Engl. J. Med. 333, 609–614 (1995).
Cole, B. F. et al. Aspirin for the chemoprevention of colorectal adenomas: meta-analysis of the randomized trials. J. Natl Cancer Inst. 101, 256–266 (2009).
Cao, Y. et al. Population-wide impact of long-term use of aspirin and the risk for cancer. JAMA Oncol. 2, 762–769 (2016).
Zelenay, S. et al. Cyclooxygenase-dependent tumor growth through evasion of immunity. Cell 162, 1257–1270 (2015).
Chan, A. T., Ogino, S. & Fuchs, C. S. Aspirin and the risk of colorectal cancer in relation to the expression of COX-2. N. Engl. J. Med. 356, 2131–2142 (2007).
Cao, Y. et al. Regular aspirin use associates with lower risk of colorectal cancers with low numbers of tumor-infiltrating lymphocytes. Gastroenterology 151, 879–892.e4 (2016).
Keum, N., Aune, D., Greenwood, D. C., Ju, W. & Giovannucci, E. L. Calcium intake and colorectal cancer risk: dose-response meta-analysis of prospective observational studies. Int. J. Cancer 135, 1940–1948 (2014).
Bristow, S. M. et al. Calcium supplements and cancer risk: a meta-analysis of randomised controlled trials. Br. J. Nutr. 110, 1384–1393 (2013).
Wactawski-Wende, J. et al. Calcium plus vitamin D supplementation and the risk of colorectal cancer. N. Engl. J. Med. 354, 684–696 (2006).
Lappe, J. et al. Effect of vitamin D and calcium supplementation on cancer incidence in older women: a randomized clinical trial. JAMA 317, 1234–1243 (2017).
Zhang, X. et al. Calcium intake and colorectal cancer risk: results from the Nurses’ Health Study and Health Professionals Follow-up Study. Int. J. Cancer 139, 2232–2242 (2016).
Keum, N., Lee, D. H., Greenwood, D. C., Zhang, X. & Giovannucci, E. L. Calcium intake and colorectal adenoma risk: dose-response meta-analysis of prospective observational studies. Int. J. Cancer 136, 1680–1687 (2015).
Veettil, S. K. et al. Effects of calcium on the incidence of recurrent colorectal adenomas: a systematic review with meta-analysis and trial sequential analysis of randomized controlled trials. Medicine 96, e7661 (2017).
Lamprecht, S. A. & Lipkin, M. Chemoprevention of colon cancer by calcium, vitamin D and folate: molecular mechanisms. Nat. Rev. Cancer 3, 601–614 (2003).
Tennakoon, S., Aggarwal, A. & Kallay, E. The calcium-sensing receptor and the hallmarks of cancer. Biochim. Biophys. Acta 1863, 1398–1407 (2016).
Ahearn, T. U., Shaukat, A., Flanders, W. D., Rutherford, R. E. & Bostick, R. M. A randomized clinical trial of the effects of supplemental calcium and vitamin D3 on the APC/β-catenin pathway in the normal mucosa of colorectal adenoma patients. Cancer Prev. Res. 5, 1247–1256 (2012).
PDQ Screening and Prevention Editorial Board. Colorectal Cancer Screening (PDQ®): Health Professional Version. PDQ Cancer Information Summaries. NIH.gov https://www.ncbi.nlm.nih.gov/books/NBK65825/ (2012).
Wieten, E. et al. Incidence of faecal occult blood test interval cancers in population-based colorectal cancer screening: a systematic review and meta-analysis. Gut 68, 873-881 (2019).
Imperiale, T. F. et al. Multitarget stool DNA testing for colorectal-cancer screening. N. Engl. J. Med. 370, 1287–1297 (2014).
Brenner, H. & Chen, H. Fecal occult blood versus DNA testing: indirect comparison in a colorectal cancer screening population. Clin. Epidemiol. 9, 377–384 (2017).
US Preventive Services Task Force, Bibbins-Domingo, K. et al. Screening for colorectal cancer: us preventive services task force recommendation statement. JAMA 315, 2564–2575 (2016).
Welch, H. G. & Black, W. C. Overdiagnosis in cancer. J. Natl Cancer Inst. 102, 605–613 (2010).
Lansdorp-Vogelaar, I., Knudsen, A. B. & Brenner, H. Cost-effectiveness of colorectal cancer screening. Epidemiol. Rev. 33, 88–100 (2011).
Tinmouth, J., Lansdorp-Vogelaar, I. & Allison, J. E. Faecal immunochemical tests versus guaiac faecal occult blood tests: what clinicians and colorectal cancer screening programme organisers need to know. Gut 64, 1327–1337 (2015).
Wolf, A. M. D. et al. Colorectal cancer screening for average-risk adults: 2018 guideline update from the American Cancer Society. CA Cancer J. Clin. 68, 250–281 (2018).
Inadomi, J. M. et al. Adherence to colorectal cancer screening: a randomized clinical trial of competing strategies. Arch. Intern. Med. 172, 575–582 (2012).
Ebell, M. H., Thai, T. N. & Royalty, K. J. Cancer screening recommendations: an international comparison of high income countries. Public Health Rev. 39, 7 (2018).
Keum, N. & Giovannucci, E. L. Folic acid fortification and colorectal cancer risk. Am. J. Prev. Med. 46, S65–S72 (2014).
Cokkinides, V., Bandi, P., Shah, M., Virgo, K. & Ward, E. The association between state mandates of colorectal cancer screening coverage and colorectal cancer screening utilization among US adults aged 50 to 64 years with health insurance. BMC Health Serv. Res. 11, 19 (2011).
James, T. M., Greiner, K. A., Ellerbeck, E. F., Feng, C. & Ahluwalia, J. S. Disparities in colorectal cancer screening: a guideline-based analysis of adherence. Ethn. Dis. 16, 228–233 (2006).
Syngal, S. et al. ACG clinical guideline: genetic testing and management of hereditary gastrointestinal cancer syndromes. Am. J. Gastroenterol. 110, 223–262; quiz 263 (2015).
Rex, D. K. et al. Colorectal cancer screening: recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastroenterology 153, 307–323 (2017).
Veronese, N. et al. Combined associations of body weight and lifestyle factors with all cause and cause specific mortality in men and women: prospective cohort study. BMJ 355, i5855 (2016).
Dulai, P. S. et al. Chemoprevention of colorectal cancer in individuals with previous colorectal neoplasia: systematic review and network meta-analysis. BMJ 355, i6188 (2016).
Cea Soriano, L., Lanas, A., Soriano-Gabarro, M. & Garcia Rodriguez, L. A. Incidence of upper and lower gastrointestinal bleeding in new users of low-dose aspirin. Clin. Gastroenterol. Hepatol. 17, 887-895.e6 (2019).
Chubak, J., Kamineni, A., Buist, D. S. M., Anderson, M. L. & Whitlock, E. P. Aspirin Use for the Prevention of Colorectal Cancer: An Updated Systematic Evidence Review for the U.S. Preventive Services Task Force (Report No.: 15-05228-EF-1), NIH.gov https://www.ncbi.nlm.nih.gov/books/NBK321661/ (2015).
Drew, D. A. et al. ASPirin Intervention for the REDuction of colorectal cancer risk (ASPIRED): a study protocol for a randomized controlled trial. Trials 18, 50 (2017).
Han, C. et al. Dietary calcium intake and the risk of colorectal cancer: a case control study. BMC Cancer 15, 966 (2015).
Shin, A. et al. Dietary intake of calcium, fiber and other micronutrients in relation to colorectal cancer risk: results from the Shanghai Women’s Health Study. Int. J. Cancer 119, 2938–2942 (2006).
Ishihara, J., Inoue, M., Iwasaki, M., Sasazuki, S. & Tsugane, S. Dietary calcium, vitamin D, and the risk of colorectal cancer. Am. J. Clin. Nutr. 88, 1576–1583 (2008).
Jones, R. M., Devers, K. J., Kuzel, A. J. & Woolf, S. H. Patient-reported barriers to colorectal cancer screening: a mixed-methods analysis. Am. J. Prev. Med. 38, 508–516 (2010).
Li, Y. et al. Impact of healthy lifestyle factors on life expectancies in the US population. Circulation 138, 345–355 (2018).
Jeon, J. et al. Determining risk of colorectal cancer and starting age of screening based on lifestyle, environmental, and genetic factors. Gastroenterology 154, 2152–2164.e19 (2018).
N.K. was supported by grants from the National Research Foundation of Korea (NRF-2018R1C1B6008822; NRF-2018R1A4A1022589).
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Nature Reviews Gastroenterology & Hepatology thanks M. Hoffmeister, and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
About this article
Cite this article
Keum, N., Giovannucci, E. Global burden of colorectal cancer: emerging trends, risk factors and prevention strategies. Nat Rev Gastroenterol Hepatol 16, 713–732 (2019). https://doi.org/10.1038/s41575-019-0189-8
The clinicopathological and prognostic significances of IGF-1R and Livin expression in patients with colorectal cancer
BMC Cancer (2022)
RNA profiling of blood platelets noninvasively differentiates colorectal cancer from healthy donors and noncancerous intestinal diseases: a retrospective cohort study
Genome Medicine (2022)
Lymphocyte antigen 6G6D-mediated modulation through p38α MAPK and DNA methylation in colorectal cancer
Cancer Cell International (2022)
Linking insulin like growth factor-1 (IGF-1) rs6214 gene polymorphism and its serum level with risk of colorectal cancer
Beni-Suef University Journal of Basic and Applied Sciences (2022)
Application of nanotechnology in the early diagnosis and comprehensive treatment of gastrointestinal cancer
Journal of Nanobiotechnology (2022)