The Colorectal Cancer Working Group

Colorectal cancer (CRC) is a common cancer in both men and women. CRC incidence rates worldwide have a large degree of heterogeneity, suggesting the etiological involvement of modifiable dietary and lifestyle risk factors. The adoption of dietary and lifestyle habits that are protective of CRC development may have considerable public health impact in reducing CRC incidence and possibly enhancing survival after diagnosis. Thus, the main objective of the Colorectal Cancer Working Group is to investigate the dietary, lifestyle, genetic, and metabolic risk factors for CRC and also to explore their underlying mechanisms of action. As of the most recent end-point update, more than 6000 CRC cases have accrued within the cohort.

The Working Group has explored the role of dietary patterns, individual food groups, specific foods, and nutrients in CRC development. Findings from EPIC on the strong inverse risk association of adherence to healthy dietary patterns (e.g. the Mediterranean diet, intake of foods with low inflammatory potential) and higher consumption of dietary fibres as well as the promoting effects of obesity, weight gain, and higher intake of processed meats have all been important evidence towards public health guidelines for CRC prevention. The Working Group has also provided strong evidence on smoking and alcohol consumption in CRC development. The term “colorectal” brings together two anatomical subsites: the colon and the rectum. Evidence generated by the Working Group suggests that they may have some heterogeneous risk factors.

The Working Group has also delved into the underlying mechanisms of these exposures, showing the CRC-promoting role of metabolic dysfunction (metabolic syndrome, hyperinsulinaemia, hyperglycaemia, dyslipidaemia, inflammation, oxidative stress), low vitamin D status, and gut barrier dysfunction, and has shown that the associations of dietary and lifestyle exposures are in part mediated via these mechanisms. The Working Group is developing considerable targeted and untargeted metabolomics data to explore metabolic pathways involved in CRC development.

EPIC also participates in several international consortia, including the NCI Cohort Consortium, the Harvard Diet and Cancer Pooling Project, and the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) on CRC genetics, pooling together data from genome-wide association studies (GWAS) worldwide to explore genetic risk and susceptibility and gene–exposure interactions in CRC development as well as application of Mendelian randomization methods for causal inference of CRC risk factors. The Working Group is currently developing new projects to explore the role of the microbiome, steroid hormones, infections, and glycation products in CRC development and the association of modifiable risk factors with CRC survival after diagnosis. There is also a growing emphasis on risk prediction. 

Selected publications

Dietary and lifestyle patterns, weight change

  1. Botteri E, Peveri G, Berstad P, Bagnardi V, Chen SLF, Sandanger TM, et al. (2023). Changes in lifestyle and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition. Am J Gastroenterol. 118(4):702–11. https://doi.org/10.14309/ajg.0000000000002065 PMID:36227801
  2. Mayén AL, Viallon V, Botteri E, Proust-Lima C, Bagnardi V, Batista V, et al. (2022). A longitudinal evaluation of alcohol intake throughout adulthood and colorectal cancer risk. Eur J Epidemiol. 37(9):915–29. https://doi.org/10.1007/s10654-022-00900-6 PMID:36063305
  3. Papadimitriou N, Bouras E, van den Brandt PA, Muller DC, Papadopoulou A, Heath AK, et al. (2022). A prospective diet-wide association study for risk of colorectal cancer in EPIC. Clin Gastroenterol Hepatol. 20(4):864–873.e13. https://doi.org/10.1016/j.cgh.2021.04.028 
    PMID:33901663
  4. Jakszyn P, Cayssials V, Buckland G, Perez-Cornago A, Weiderpass E, Boeing H, et al. (2020). Inflammatory potential of the diet and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study. Int J Cancer. 147(4):1027–39. https://doi.org/10.1002/ijc.32870 PMID:31945199
  5. Romaguera D, Ward H, Wark PA, Vergnaud AC, Peeters PH, van Gils CH, et al. (2015). Pre-diagnostic concordance with the WCRF/AICR guidelines and survival in European colorectal cancer patients: a cohort study. BMC Med. 13(1):107. https://doi.org/10.1186/s12916-015-0332-5 PMID:25948112
  6. Steins Bisschop CN, van Gils CH, Emaus MJ, Bueno-de-Mesquita HB, Monninkhof EM, Boeing H, et al. (2014). Weight change later in life and colon and rectal cancer risk in participants in the EPIC-PANACEA study. Am J Clin Nutr. 99(1):139–47. https://doi.org/10.3945/ajcn.113.066530 PMID:24225355
  7. Romaguera D, Vergnaud AC, Peeters PH, van Gils CH, Chan DS, Ferrari P, et al. (2012). Is concordance with World Cancer Research Fund/American Institute for Cancer Research guidelines for cancer prevention related to subsequent risk of cancer? Results from the EPIC study. Am J Clin Nutr. 96(1):150–63. https://doi.org/10.3945/ajcn.111.031674 PMID:22592101

Genetic and gene–exposure interactions

  1. Nimptsch K, Aleksandrova K, Fedirko V, Jenab M, Gunter MJ, Siersema PD, et al. (2022). Pre-diagnostic C-reactive protein concentrations, CRP genetic variation and mortality among individuals with colorectal cancer in Western European populations. BMC Cancer. 22(1):695. https://doi.org/10.1186/s12885-022-09778-9 PMID:35739525
  2. Fedirko V, Jenab M, Méplan C, Jones JS, Zhu W, Schomburg L, et al. (2019). Association of selenoprotein and selenium pathway genotypes with risk of colorectal cancer and interaction with selenium status. Nutrients. 11(4):935. https://doi.org/10.3390/nu11040935 PMID:31027226
  3. Jenab M, McKay J, Bueno-de-Mesquita HB, van Duijnhoven FJ, Ferrari P, Slimani N, et al. (2009). Vitamin D receptor and calcium sensing receptor polymorphisms and the risk of colorectal cancer in European populations. Cancer Epidemiol Biomarkers Prev. 18(9):2485–91. https://doi.org/10.1158/1055-9965.EPI-09-0319 PMID:19706842

 

Dietary variables, foods, food groups, and nutrients

  1. Rothwell JA, Bešević J, Dimou N, Breeur M, Murphy N, Jenab M, et al. (2023). Circulating amino acid levels and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition and UK Biobank cohorts. BMC Med. 21(1):80. https://doi.org/10.1186/s12916-023-02739-4 PMID:36855092
  2. Karavasiloglou N, Hughes DJ, Murphy N, Schomburg L, Sun Q, Seher V, et al. (2023). Prediagnostic serum calcium concentrations and risk of colorectal cancer development in 2 large European prospective cohorts. Am J Clin Nutr. 117(1):33–45. https://doi.org/10.1016/j.ajcnut.2022.10.004 PMID:36789942
  3. Aglago EK, Cross AJ, Riboli E, Fedirko V, Hughes DJ, Fournier A, et al. (2023). Dietary intake of total, heme and non-heme iron and the risk of colorectal cancer in a European prospective cohort study. Br J Cancer. 128(8):1529–40. https://doi.org/10.1038/s41416-023-02164-7 PMID:36759722
  4. Mao Z, Baker JR, Takeuchi M, Hyogo H, Tjønneland A, Eriksen AK, et al. (2023). Prediagnostic serum glyceraldehyde-derived advanced glycation end products and mortality among colorectal cancer patients. Int J Cancer. 152(11):2257–68. https://doi.org/10.1002/ijc.34449 PMID:36715363
  5. Mao Z, Aglago EK, Zhao Z, Schalkwijk C, Jiao L, Freisling H, et al. (2021). Dietary intake of advanced glycation end products (AGEs) and mortality among individuals with colorectal cancer. Nutrients. 13(12):4435. https://doi.org/10.3390/nu13124435 PMID:34959986
  6. Baker JR, Umesh S, Jenab M, Schomburg L, Tjønneland A, Olsen A, et al. (2021). Prediagnostic blood selenium status and mortality among patients with colorectal cancer in Western European populations. Biomedicines. 9(11):1521. https://doi.org/10.3390/biomedicines9111521 PMID:34829750
  7. Aglago EK, Mayén AL, Knaze V, Freisling H, Fedirko V, Hughes DJ, et al. (2021). Dietary advanced glycation end-products and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Nutrients. 13(9):3132. https://doi.org/10.3390/nu13093132 PMID:34579010
  8. Aglago EK, Murphy N, Huybrechts I, Nicolas G, Casagrande C, Fedirko V, et al. (2021). Dietary intake and plasma phospholipid concentrations of saturated, monounsaturated and trans fatty acids and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort. Int J Cancer. 149(4):865–82. https://doi.org/10.1002/ijc.33615 PMID:33913149
  9. Aglago EK, Schalkwijk CG, Freisling H, Fedirko V, Hughes DJ, Jiao L, et al. (2021). Plasma concentrations of advanced glycation end-products and colorectal cancer risk in the EPIC study. Carcinogenesis. 42(5):705–13. https://doi.org/10.1093/carcin/bgab026 PMID:33780524
  10. Aglago EK, Huybrechts I, Murphy N, Casagrande C, Nicolas G, Pischon T, et al. (2020). Consumption of fish and long-chain n-3 polyunsaturated fatty acids is associated with reduced risk of colorectal cancer in a large European cohort. Clin Gastroenterol Hepatol. 18(3):654–666.e6. https://doi.org/10.1016/j.cgh.2019.06.031 PMID:31252190
  11. Ward HA, Norat T, Overvad K, Dahm CC, Bueno-de-Mesquita HB, Jenab M, et al. (2016). Pre-diagnostic meat and fibre intakes in relation to colorectal cancer survival in the European Prospective Investigation into Cancer and Nutrition. Br J Nutr. 116(2):316–25. https://doi.org/10.1017/S0007114516001859 PMID:27193442
  12. Leenders M, Siersema PD, Overvad K, Tjønneland A, Olsen A, Boutron-Ruault MC, et al. (2015). Subtypes of fruit and vegetables, variety in consumption and risk of colon and rectal cancer in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 137(11):2705–14. https://doi.org/10.1002/ijc.29640 PMID:26077137
  13. Hughes DJ, Fedirko V, Jenab M, Schomburg L, Méplan C, Freisling H, et al. (2015). Selenium status is associated with colorectal cancer risk in the European prospective investigation of cancer and nutrition cohort. Int J Cancer. 136(5):1149–61. https://doi.org/10.1002/ijc.29071 PMID:25042282
  14. Ferrari P, Licaj I, Muller DC, Kragh Andersen P, Johansson M, Boeing H, et al. (2014). Lifetime alcohol use and overall and cause-specific mortality in the European Prospective Investigation into Cancer and nutrition (EPIC) study. BMJ Open. 4(7):e005245. https://doi.org/10.1136/bmjopen-2014-005245 PMID:24993766
  15. Kyrø C, Olsen A, Landberg R, Skeie G, Loft S, Åman P, et al. (2014). Plasma alkylresorcinols, biomarkers of whole-grain wheat and rye intake, and incidence of colorectal cancer. J Natl Cancer Inst. 106(1):djt352. https://doi.org/10.1093/jnci/djt352 PMID:24317181

Metabolic factors

  1. Pham TT, Nimptsch K, Aleksandrova K, Jenab M, Reichmann R, Wu K, et al. (2022). Pre-diagnostic circulating resistin concentrations are not associated with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition study. Cancers (Basel). 14(22):5499. https://doi.org/10.3390/cancers14225499 PMID:36428592
  2. Kliemann N, Viallon V, Murphy N, Beeken RJ, Rothwell JA, Rinaldi S, et al. (2021). Metabolic signatures of greater body size and their associations with risk of colorectal and endometrial cancers in the European Prospective Investigation into Cancer and Nutrition. BMC Med. 19(1):101. https://doi.org/10.1186/s12916-021-01970-1 PMID:33926456
  3. Kühn T, Stepien M, López-Nogueroles M, Damms-Machado A, Sookthai D, Johnson T, et al. (2020). Prediagnostic plasma bile acid levels and colon cancer risk: a prospective study. J Natl Cancer Inst. 112(5):516–24. https://doi.org/10.1093/jnci/djz166 PMID:31435679
  4. Ward HA, Murphy N, Weiderpass E, Leitzmann MF, Aglago E, Gunter MJ, et al. (2019). Gallstones and incident colorectal cancer in a large pan-European cohort study. Int J Cancer. 145(6):1510–6. https://doi.org/10.1002/ijc.32090 PMID:30585640
  5. Murphy N, Cross AJ, Abubakar M, Jenab M, Aleksandrova K, Boutron-Ruault MC, et al. (2016). A nested case-control study of metabolically defined body size phenotypes and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC). PLoS Med. 13(4):e1001988. https://doi.org/10.1371/journal.pmed.1001988 PMID:27046222
  6. Kong SY, Tran HQ, Gewirtz AT, McKeown-Eyssen G, Fedirko V, Romieu I, et al. (2016). Serum endotoxins and flagellin and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Cancer Epidemiol Biomarkers Prev. 25(2):291–301. https://doi.org/10.1158/1055-9965.EPI-15-0798 PMID:26823475
  7. Kong SY, Takeuchi M, Hyogo H, McKeown-Eyssen G, Yamagishi S, Chayama K, et al. (2015). The association between glyceraldehyde-derived advanced glycation end-products and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev. 24(12):1855–63. https://doi.org/10.1158/1055-9965.EPI-15-0422 PMID:26404963
  8. Aleksandrova K, Chuang SC, Boeing H, Zuo H, Tell GS, Pischon T, et al. (2015). A prospective study of the immune system activation biomarker neopterin and colorectal cancer risk. J Natl Cancer Inst. 107(4):djv010. https://doi.org/10.1093/jnci/djv010 PMID:25713165
  9. Nimptsch K, Aleksandrova K, Boeing H, Janke J, Lee YA, Jenab M, et al. (2015). Plasma fetuin-A concentration, genetic variation in the AHSG gene and risk of colorectal cancer. Int J Cancer. 137(4):911–20. https://doi.org/10.1002/ijc.29448 PMID:25611809
  10. Aleksandrova K, Boeing H, Jenab M, Bueno-de-Mesquita HB, Jansen E, van Duijnhoven FJ, et al. (2012). Leptin and soluble leptin receptor in risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition cohort. Cancer Res. 72(20):5328–37. https://doi.org/10.1158/0008-5472.CAN-12-0465 PMID:22926557
  11. van Duijnhoven FJ, Bueno-De-Mesquita HB, Calligaro M, Jenab M, Pischon T, Jansen EH, et al. (2011). Blood lipid and lipoprotein concentrations and colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition. Gut. 60(8):1094–102. https://doi.org/10.1136/gut.2010.225011 PMID:21383385
  12. Jenab M, Bueno-de-Mesquita HB, Ferrari P, van Duijnhoven FJ, Norat T, Pischon T, et al. (2010). Association between pre-diagnostic circulating vitamin D concentration and risk of colorectal cancer in European populations: a nested case-control study. BMJ. 340:b5500. https://doi.org/10.1136/bmj.b5500 PMID:20093284

Anatomical subsites and reproductive history

  1. Murphy N, Ward HA, Jenab M, Rothwell JA, Boutron-Ruault MC, Carbonnel F, et al. (2019). Heterogeneity of colorectal cancer risk factors by anatomical subsite in 10 European countries: a multinational cohort study. Clin Gastroenterol Hepatol. 17(7):1323–1331.e6. https://doi.org/10.1016/j.cgh.2018.07.030 PMID:30056182
  2. Tsilidis KK, Allen NE, Key TJ, Sanjoaquin MA, Bakken K, Berrino F, et al. (2011). Menopausal hormone therapy and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition. Int J Cancer. 128(8):1881–9. https://doi.org/10.1002/ijc.25504 PMID:20533550


Consortia and pooling projects, Mendelian randomization approaches

  1. Papadimitriou N, Bull CJ, Jenab M, Hughes DJ, Bell JA, Sanderson E, et al. (2023). Separating the effects of early and later life adiposity on colorectal cancer risk: a Mendelian randomization study. BMC Med. 21(1):5. https://doi.org/10.1186/s12916-022-02702-9 PMID:36600297
  2. Seyed Khoei N, Jenab M, Murphy N, Banbury BL, Carreras-Torres R, Viallon V, et al. (2020). Circulating bilirubin levels and risk of colorectal cancer: serological and Mendelian randomization analyses. BMC Med. 18(1):229. https://doi.org/10.1186/s12916-020-01703-w PMID:32878631
  3. Papadimitriou N, Dimou N, Tsilidis KK, Banbury B, Martin RM, Lewis SJ, et al. (2020). Physical activity and risks of breast and colorectal cancer: a Mendelian randomisation analysis. Nat Commun. 11(1):597. https://doi.org/10.1038/s41467-020-14389-8 PMID:32001714
  4. Murphy N, Carreras-Torres R, Song M, Chan AT, Martin RM, Papadimitriou N, et al. (2020). Circulating levels of insulin-like growth factor 1 and insulin-like growth factor binding protein 3 associate with risk of colorectal cancer based on serologic and Mendelian randomization analyses. Gastroenterology. 158(5):1300–1312.e20. https://doi.org/10.1053/j.gastro.2019.12.020 PMID:31884074
  5. Archambault AN, Su YR, Jeon J, Thomas M, Lin Y, Conti DV, et al. (2020). Cumulative burden of colorectal cancer-associated genetic variants is more strongly associated with early-onset vs late-onset cancer. Gastroenterology. 158(5):1274–1286.e12. https://doi.org/10.1053/j.gastro.2019.12.012 PMID:31866242
  6. Huyghe JR, Bien SA, Harrison TA, Kang HM, Chen S, Schmit SL, et al. (2019). Discovery of common and rare genetic risk variants for colorectal cancer. Nat Genet. 51(1):76–87. https://doi.org/10.1038/s41588-018-0286-6 PMID:30510241
  7. McCullough ML, Zoltick ES, Weinstein SJ, Fedirko V, Wang M, Cook NR, et al. (2019). Circulating vitamin D and colorectal cancer risk: an international pooling project of 17 cohorts. J Natl Cancer Inst. 111(2):158–69. https://doi.org/10.1093/jnci/djy087 PMID:29912394


Infections and the microbiome

  1. Kliemann N, Viallon V, Murphy N, Beeken RJ, Rothwell JA, Rinaldi S, et al. (2021). Metabolic signatures of greater body size and their associations with risk of colorectal and endometrial cancers in the European Prospective Investigation into Cancer and Nutrition. BMC Med. 19(1):101. https://doi.org/10.1186/s12916-021-01970-1 PMID:33926456
  2. Butt J, Jenab M, Willhauck-Fleckenstein M, Michel A, Pawlita M, Kyrø C, et al. (2018). Prospective evaluation of antibody response to Streptococcus gallolyticus and risk of colorectal cancer. Int J Cancer. 143(2):245–52. https://doi.org/10.1002/ijc.31283 PMID:29377173


Mediation analyses

  1. Aleksandrova K, Jenab M, Leitzmann M, Bueno-de-Mesquita B, Kaaks R, Trichopoulou A, et al. (2017). Physical activity, mediating factors and risk of colon cancer: insights into adiposity and circulating biomarkers from the EPIC cohort. Int J Epidemiol. 46(6):1823–35. https://doi.org/10.1093/ije/dyx174 PMID:29025032
  2. Aleksandrova K, Schlesinger S, Fedirko V, Jenab M, Bueno-de-Mesquita B, Freisling H, et al. (2017). Metabolic mediators of the association between adult weight gain and colorectal cancer: data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Am J Epidemiol. 185(9):751–64. https://doi.org/10.1093/aje/kww194 PMID:28387787
     

Contact details/Working Group leaders

Professor Marc Gunter, PhD
School of Public Health, Faculty of Medicine
Imperial College London
Norfolk Place, London W2 1PG
United Kingdom
m.gunter@imperial.ac.uk

Mazda Jenab, PhD
Team Leader, Onco-Metabolomics Team (OMB), Nutrition and Metabolism Branch (NME)
International Agency for Research on Cancer (IARC/WHO)
25 avenue Tony Garnier
CS 90627
69366 LYON CEDEX 07
France
JenabM@iarc.who.int

Professor Amanda Cross, PhD
Cancer Screening and Prevention Research Group
School of Public Health and the Department of Surgery and Cancer
Imperial College London
Norfolk Place, London W2 1PG
United Kingdom
amanda.cross@imperial.ac.uk