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      Substantial contribution of extrinsic risk factors to cancer development

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      Author(s): 1 , 2 , 2 , 3 , 1 , 2 , 2 , 4
      Publication date (Electronic):
      Journal: Nature

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          Summary

          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 dissemination of the ‘bad luck’ hypothesis. Here we provide evidence that intrinsic risk factors contribute only modestly (<10~30%) 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. Next, we 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 carry immense consequences for strategizing cancer prevention, research, and public health.

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          Most cited references27

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          Colorectal cancer epidemiology: incidence, mortality, survival, and risk factors.

          Fatima Haggar, Robin P Boushey (2009)
          In this article, the incidence, mortality, and survival rates for colorectal cancer are reviewed, with attention paid to regional variations and changes over time. A concise overview of known risk factors associated with colorectal cancer is provided, including familial and hereditary factors, as well as environmental lifestyle-related risk factors such as physical inactivity, obesity, smoking, and alcohol consumption.
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            Cancer etiology. Variation in cancer risk among tissues can be explained by the number of stem cell divisions.

            Cristian Tomasetti, Bert Vogelstein (2015)
            Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue's homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to "bad luck," that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes. Copyright © 2015, American Association for the Advancement of Science.
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              Smoking and drinking in relation to oral and pharyngeal cancer.

              W J Blot, J McLaughlin, D M Winn … (1988)
              A case-control study of oral and pharyngeal cancer conducted in four areas of the United States provided information on the tobacco and alcohol use of 1114 patients and 1268 population-based controls. Because of the large study size, it could be shown that the risks of these cancers among nondrinkers increased with amount smoked, and conversely that the risks among nonsmokers increased with the level of alcohol intake. Among consumers of both products, risks of oropharyngeal cancer tended to combine more in a multiplicative than additive fashion and were increased more than 35-fold among those who consumed two or more packs of cigarettes and more than four alcoholic drinks/day. Cigarette, cigar, and pipe smoking were separately implicated, although it was shown for the first time that risk was not as high among male lifelong filter cigarette smokers. Cessation of smoking was associated with a sharply reduced risk of this cancer, with no excess detected among those having quit for 10 or more years, suggesting that smoking affects primarily a late stage in the process of oropharyngeal carcinogenesis. The risks varied by type of alcoholic beverage, being higher among those consuming hard liquor or beer than wine. The relative risk patterns were generally similar among whites and blacks, and among males and females, and showed little difference when oral and pharyngeal cancers were analyzed separately. From calculations of attributable risk, we estimate that tobacco smoking and alcohol drinking combine to account for approximately three-fourths of all oral and pharyngeal cancers in the United States.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 0410462
                Journal ID (pubmed-jr-id): 6011
                Journal ID (nlm-ta): Nature
                Journal ID (iso-abbrev): Nature
                Title: Nature
                ISSN (Print): 0028-0836
                ISSN (Electronic): 1476-4687
                Publication date Nihms-submitted: 27 October 2015
                Publication date (Electronic): 16 December 2015
                Publication date (Print): 7 January 2016
                Publication date PMC-release: 16 June 2016
                Volume: 529
                Issue: 7584
                Pages: 43-47
                Affiliations
                [1 ]Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York 11794
                [2 ]Stony Brook Cancer Center, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794
                [3 ]Department of Pathology, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794
                [4 ]Department of Medicine, Stony Brook University, Health Sciences Center, Stony Brook, New York 11794
                Author notes
                Author Contact: Yusuf A Hannun, MD, Director, Stony Brook Cancer Center, Joel Kenny Professor of Medicine, Health Sciences Center L-4, 182, Stony Brook University School of Medicine, Stony Brook, NY 11794-8430, Yusuf.Hannun@ 123456sbumed.org , Telephone: 631-444-8067, Fax: 631-444-2661
                Correspondence and requests for materials should be addressed to: Song.Wu@ 123456stonybrook.edu or Yusuf.Hannun@ 123456sbumed.org
                Article
                Manuscript ID: NIHMS733229
                DOI: 10.1038/nature16166
                PMC ID: 4836858
                PubMed ID: 26675728
                SO-VID: a6b70279-3adb-4205-a49c-9f92339cdc16
                License:

                Reprints and permissions information is available at www.nature.com/reprints.

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