title: Substantial contribution of extrinsic risk factors to cancer development.
abstract: Recent research has highlighted a strong correlation between tissue-specific cancer risk and the lifetime number of tissue-specific stem-cell divisions. Whether such correlation implies a high unavoidable intrinsic cancer risk has become a key public health debate with the dissemination of the 'bad luck' hypothesis. Here we provide evidence that intrinsic risk factors contribute only modestly (less than ~10-30% of lifetime risk) to cancer development. First, we demonstrate that the correlation between stem-cell division and cancer risk does not distinguish between the effects of intrinsic and extrinsic factors. We then show that intrinsic risk is better estimated by the lower bound risk controlling for total stem-cell divisions. Finally, we show that the rates of endogenous mutation accumulation by intrinsic processes are not sufficient to account for the observed cancer risks. Collectively, we conclude that cancer risk is heavily influenced by extrinsic factors. These results are important for strategizing cancer prevention, research and public health.
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York 11794, USA.|Stony Brook Cancer Center, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794, USA.
authors.forename: Song
authors.initials: S
authors.lastname: Wu
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York 11794, USA.|Stony Brook Cancer Center, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794, USA.|Department of Pathology, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794, USA.
authors.forename: Scott
authors.initials: S
authors.lastname: Powers
authors.affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York 11794, USA.|Stony Brook Cancer Center, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.affiliation: Stony Brook Cancer Center, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794, USA.|Department of Pathology, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794, USA.|Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794, USA.|Department of Biochemistry, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794, USA.
authors.forename: Yusuf A
authors.initials: YA
authors.lastname: Hannun
mesh_terms: D000066673:Cell Self Renewal; D002471:Cell Transformation, Neoplastic / Q000473:pathology; D018450:Disease Progression; D006801:Humans; D008954:Models, Biological; D016296:Mutagenesis / Q000235:genetics; D000067552:Mutation Accumulation; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D009928:Organ Specificity; D015203:Reproducibility of Results; D018570:Risk Assessment; D013234:Stem Cells / Q000166:cytology* / Q000473:pathology