The role of chance in cancer causation

Main Article Content

Marco Angelini
Giulia Collatuzzo
Federica Teglia
Michele Sassano
Andrei Cosmin Siea
Paolo Boffetta


cancer epidemiology;, cancer causation;, role of chance;, risk factors;, cancer onset;


In the last years, the discussion about the role of chance in the causation of cancer has generated much scientific and public debate. The concept that chance, or “bad luck”, as responsible for a majority of the variation of cancer incidence, may be misleading, possibly causing an underestimation of the role played by known risk factors. In this commentary we discuss how host and external factors interact with chance in cancer causation in different ways, and provide examples of situations where chance appears to play only a minor role on cancer onset.


Download data is not yet available.
Abstract 225 | PDF Downloads 238


1. Perduca V, Alexandrov LB, Kelly-Irving M, et al. Stem cell replication, somatic mutations and role of randomness in the development of cancer. Eur J Epidemiol. 2019;34(5):439-445.
2. Weinberg CR, Zaykin D. Is bad luck the main cause of cancer?. J Natl Cancer Inst. 2015;107(7):djv125. Published 2015 May 8.
3. Luzzatto L, Pandolfi PP. Causality and Chance in the Development of Cancer. N Engl J Med. 2015;373(1):84-88.
4. Tomasetti C, Vogelstein B. Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science. 2015;347(6217):78-81.
5. Tomasetti C, Li L, Vogelstein B. Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science. 2017;355(6331):1330-1334.
6. Couzin-Frankel J. Science Communication. Backlash greets “bad luck” cancer study and coverage. Sci-ence. 2015;347(6219):224. Doi:10.1126/science.347.6219.224
7. Rozhok AI, Wahl GM, DeGregori J. A Critical Examination of the “Bad Luck” Explanation of Cancer Risk. Cancer Prev Res (Phila). 2015;8(9):762-764.
8. Most types of cancer not due to “bad luck” IARC responds to scientific article claiming that environ-mental and lifestyle factors account for less than one third of cancers. Cent Eur J Public Health. 2015; 23(1):87.
9. Wu S, Powers S, Zhu W, Hannun YA. Substantial contribution of extrinsic risk factors to cancer devel-opment. Nature. 2016;529(7584):43-47.
10. Thomas F, Roche B, Ujvari B. Intrinsic versus Extrinsic Cancer Risks: The Debate Continues. Trends Cancer. 2016;2(2):68-69. doi:10.1016/j.trecan.2016.01.004
11. Hanahan D, Weinberg RA. The hallmarks of cancer. Cell. 2000;100(1):57-70.
12. Armitage P, Doll R. A two-stage theory of carcinogenesis in relation to the age distribution of human cancer. Br J Cancer. 1957;11(2):161-9.
13. Amosite asbestos and mesothelioma. Lancet. 1981;2(8260-61):1397-1398.
14. Meng C, Bai C, Brown TD, et al. Human Gut Microbiota and Gastrointestinal Cancer. Genomics Prote-omics Bioinformatics. 2018;16(1):33-49.
15. IARC monographs on the identification of carcinogenic hazards to humans Last accessed 30 Oct 2022.
16. Kusiak RA, Springer J, Ritchie AC, et al. Carcinoma of the lung in Ontario gold miners: possible aetiolog-ical factors. Br J Ind Med. 1991;48(12):808-817.
17. Pearlman R, Frankel WL, Swanson B, et al. Prevalence and Spectrum of Germline Cancer Susceptibility Gene Mutations Among Patients With Early-Onset Colorectal Cancer. JAMA Oncol. 2017;3(4):464-471.
18. Tindle HA, Stevenson Duncan M, Greevy RA, et al. Lifetime Smoking History and Risk of Lung Cancer: Results From the Framingham Heart Study. J Natl Cancer Inst. 2018;110(11):1201-1207.
19. Hueper WC, Wiley F, Wolfe HD. Experimental production of bladder tumors in dogs by administration of beta-naphthylamine. J Ind Hyg Toxicol. 20:46-84 (1938).
20. Case RA, Hosker ME, McDonald DB, Pearson JT. Tumours of the urinary bladder in workmen engaged in the manufacture and use of certain dyestuff intermediates in the British chemical industry. I. The role of aniline, benzidine, alpha-naphthylamine, and beta-naphthylamine. Br J Ind Med. 1954;11(2): 75-104.
21. Vineis P, Pirastu R. Aromatic amines and cancer. Cancer Causes Control. 1997;8(3):346-355.
22. Case RA. Tumours of the urinary tract as an occupational disease in several industries. Ann R Coll Surg Engl. 1966 Oct;39(4):213-35.
23. Xie C, Lu H, Nomura A, et al. Co-deleting Pten with Rb in retinal progenitor cells in mice results in fully penetrant bilateral retinoblastomas. Mol Cancer. 2015;14:93. Published 2015 Apr 24.
24. Draper GJ, Sanders BM, Brownbill PA, et al. Patterns of risk of hereditary retinoblastoma and applica-tions to genetic counselling. Br J Cancer. 1992;66(1):211-219.
25. Ries LAG, Smith MA, Gurney JG, et al. Cancer incidence and survival among children and adolescents: United States SEER program 1975-1995. Bethesda, (MD): National Cancer Institute, SEER Program; 1999, p. 182.
26. Bassett JH, Forbes SA, Pannett AA, et al. Characterization of mutations in patients with multiple endo-crine neoplasia type 1. Am J Hum Genet. 1998;62(2):232-244.
27. Marx SJ, Vinik AI, Santen RJ, et al. Multiple endocrine neoplasia type I: assessment of laboratory tests to screen for the gene in a large kindred. Medicine (Baltimore). 1986;65(4):226-41.
28. McDonnell JE, Gild ML, Clifton-Bligh RJ, et al. Multiple endocrine neoplasia: an update. Intern Med J. 2019;49(8):954-961.
29. Bim LV, Navarro FCP, Valente FOF, et al. Retroposed copies of RET gene: a somatically acquired event in medullary thyroid carcinoma. BMC Med Genomics. 2019 Jul 9;12(1):104.
30. Czyz W, Morahan JM, Ebers GC, et al. Genetic, environmental and stochastic factors in monozygotic twin discordance with a focus on epigenetic differences. BMC Med. 2012 Aug 17;10:93.
31. Biwer C, Kawam B, Chapelle V, et al. The Role of Stochasticity in the Origin of Epigenetic Variation in Animal Populations. Integr Comp Biol. 2020 Dec 16;60(6):1544-1557.
32. Ushijima T, Watanabe N, Okochi E, et al. Fidelity of the methylation pattern and its variation in the ge-nome. Genome Res. 2003;13(5):868-874.
33. Mai PL, Best AF, Peters JA, et al. Risks of first and subsequent cancers among TP53 mutation carriers in the National Cancer Institute Li-Fraumeni syndrome cohort. Cancer. 2016;122(23):3673-3681.
34. Schneider K, Zelley K, Nichols KE, Garber J. Li-Fraumeni Syndrome. In: Adam MP, Everman DB, Mirzaa GM, et al., eds. GeneReviews®. Seattle (WA): University of Washington, Seattle; January 19, 1999.
35. Werner H, Lapkina-Gendler L, Achlaug L, et al. Genome-Wide Profiling of Laron Syndrome Patients Identifies Novel Cancer Protection Pathways. Cells. 2019 Jun 15;8(6):596.
36. Benyi E, Linder M, Adami J, Kieler H, Palme M, Sävendahl L. Adult height is associated with risk of can-cer and mortality in 5.5 million Swedish women and men. J Epidemiol Community Health. 2019 Aug;73(8):730-736.
37. Rafalko J, Kruglyak K, McCleary-Wheeler A et al. Age at cancer diagnosis by breed, weight, sex, and cancer type in a cohort of over 3,000 dogs: determining the optimal age to initiate cancer screening in canine patients. bioRxiv 2022.03.30.486448
38. Martineau D, Lemberger K, Dallaire A, et al. Cancer in wildlife, a case study: beluga from the St. Law-rence estuary, Québec, Canada. Environ Health Perspect. 2002 Mar;110(3):285-92.
39. Peto R, Roe FJ, Lee PN, et al. Cancer and ageing in mice and men. Br J Cancer. 1975 Oct;32(4):411-26.
40. Abegglen LM, Caulin AF, Chan A et al. Potential Mechanisms for Cancer Resistance in Elephants and Comparative Cellular Response to DNA Damage in Humans. JAMA. 2015 Nov 3;314(17):1850-60.
41. Ferlay J, Laversanne M, Ervik M, et al (2020). Global Cancer Observatory: Cancer Tomorrow. Lyon, France: International Agency for Research on Cancer. Available from:, accessed October 15 2022.
42. Sulak M, Fong L, Mika K, et al. TP53 copy number expansion is associated with the evolution of in-creased body size and an enhanced DNA damage response in elephants. Elife. 2016 Sep 19;5:e11994.
43. Dunn GP, Bruce AT, Ikeda H, et al. Cancer immunoediting: from immunosurveillance to tumor escape. Nat Immunol. 2002 Nov;3(11):991-8.
44. Reynolds I, Healy P, Mcnamara DA. Malignant tumours of the small intestine. Surgeon. 2014;12(5):263-270.
45. Helander HF, Fändriks L. Surface area of the digestive tract – revisited. Scand J Gastroenterol. 2014;49(6): 681-689.
46. Wan Q, Zhao R, Xia L, et al. Inflammatory bowel disease and risk of gastric, small bowel and colorectal cancer: a meta-analysis of 26 observational studies. J Cancer Res Clin Oncol. 2021;147(4):1077-1087.
47. Neugut AI, Jacobson JS, Suh S, et al. The epidemiology of cancer of the small bowel. Cancer Epidemiol Biomarkers Prev. 1998;7(3):243-251.
48. Bray F, Colombet M, Mery L, et al. (2017). Cancer Incidence in Five Continents, Vol. XI (electronic ver-sion). Lyon: International Agency for Research on Cancer. Available at:
49. Sun S, Osterman MD, Li M. Tissue specificity of DNA damage response and tumorigenesis. Cancer Biol Med. 2019 Aug;16(3):396-414.
50. Blanpain C, Mohrin M, Sotiropoulou PA, et al. DNA-damage response in tissue-specific and cancer stem cells. Cell Stem Cell. 2011 Jan 7;8(1):16-29.
51. Haselkorn T, Whittemore AS, Lilienfeld DE. Incidence of small bowel cancer in the United States and worldwide: geographic, temporal, and racial differences. Cancer Causes Control. 2005;16(7):781-7.
52. Schrock AB, Devoe CE, McWilliams R, et al. Genomic Profiling of Small-Bowel Adenocarcinoma. JAMA Oncol. 2017;3(11):1546-1553.
53. Boffetta P, Farioli A, Rizzello E. Application of epidemiological findings to individuals. Med Lav. 2020;111(1):10-21.
54. Li Y, Liang M, Mao L, et al. Robust estimation and variable selection for the accelerated failure time model. Stat Med. 2021;40(20):4473-4491.
55. Stanta G, Campagner L, Cavallieri F, et al. Cancer of the oldest old. What we have learned from autopsy studies. Clin Geriatr Med. 1997 Feb;13(1):55-68.
56. Saltzstein SL, Behling CA, Baergen RN. Features of cancer in nonagenarians and centenarians. J Am Geriatr Soc. 1998 Aug;46(8):994-8.
57. Andersen SL, Terry DF, Wilcox MA, et al. Cancer in the oldest old. Mech Ageing Dev. 2005;126(2):263-7.
58. Arbeev K, Ukraintseva S, Arbeeva LS, et al. 2005. Decline in Human Cancer Incidence Rates at Old Ages: Age-Period-Cohort Considerations, Demographic Research, Max Planck Institute for Demographic Research, Rostock, Germany, 2005;12(11):273-300.
59. Harding C, Pompei F, Lee EE, Wilson R. Cancer suppression at old age. Cancer Res. 2008 Jun 1;68(11):4465-78.
60. Hashim D, Carioli G, Malvezzi M, et al. Cancer mortality in the oldest old: a global overview. Aging (Al-bany NY). 2020 Sep 3;12(17):16744-16758.
61. Siu AL. US Preventive Services Task Force. Screening for Breast Cancer: US Preventive Services Task Force Recommendation Statement [published correction appears in Ann Intern Med. 2016 Mar 15;164(6):448]. Ann Intern Med. 2016;164(4):279-296.
62. Davidson KW, Barry MJ, Mangione CM, et al. US Preventive Services Task Force. Screening for colorec-tal cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(19):1965-1977.
63. Curry SJ, Krist AH, Owens DK, et al. US Preventive Services Task Force. Screening for cervical cancer: US Preventive Services Task Force recommendation statement. JAMA. 2018;320(7):674-686.
64. Lee EH, Han MA, Lee HY, et al. Liver cancer screening in Korea: a report on the 2008 National Cancer Screening Programme. Asian Pac J Cancer Prev. 2010;11(5):1305-1310.
65. Setoyama H, Tanaka Y, Kanto T. Seamless support from screening to anti-HCV treatment and HCC/ decompensated cirrhosis: Subsidy programs for HCV elimination. Glob Health Med. 2021;3(5):335-342.
66. Hoffman RM, Sanchez R. Lung Cancer Screening. Med Clin North Am. 2017;101(4):769-785.
67. Wood DE, Kazerooni EA, Baum SL, et al. Lung Cancer Screening, Version 3.2018, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16(4):412-441.
68. Krist AH, Davidson KW, Mangione CM, et al. US Preventive Services Task Force. Screening for lung cancer: US Preventive Services Task Force recommendation statement. JAMA. 2021;325(10):962-970.
69. Leja M, Grinberga-Derica I, Bilgilier C, et al. Review: Epidemiology of Helicobacter pylori infection. Helicobacter. 2019;24(Suppl 1):e12635.
70. Fuccio L, Zagari RM, Eusebi LH,et al. Meta-analysis: can Helicobacter pylori eradication treatment re-duce the risk for gastric cancer? Ann. Intern. Med. 2009;151:121-128.
71. Liou JM, Malfertheiner P, Lee YC, et al. Screening and eradication of Helicobacter pylori for gastric can-cer prevention: the Taipei global consensus. Gut. 2020;69(12):2093-2112.