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Substantial contribution of extrinsic risk factors to cancer development.

Wu S, Powers S, Zhu W, Hannun YA - Nature (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York 11794, USA.

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.

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Correlation analysis of stem-cell division and cancer risk does not distinguish contribution of extrinsic vs. intrinsic factors to cancer riskThe black dots are data in Fig. 1 (also tabulated in Supplementary Table S1) of the original work by Tomasetti and Vogelstein5. The black line was their original regression line. The blue diamonds represent the hypothesized quadrupled cancer risks due to hypothetical exposure to an extrinsic factor such as radiation. The blue regression line for the hypothetical risk data maintains the same correlation as the original black line, albeit reflecting a much higher contribution of extrinsic factors to cancer risk.
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Figure 2: Correlation analysis of stem-cell division and cancer risk does not distinguish contribution of extrinsic vs. intrinsic factors to cancer riskThe black dots are data in Fig. 1 (also tabulated in Supplementary Table S1) of the original work by Tomasetti and Vogelstein5. The black line was their original regression line. The blue diamonds represent the hypothesized quadrupled cancer risks due to hypothetical exposure to an extrinsic factor such as radiation. The blue regression line for the hypothetical risk data maintains the same correlation as the original black line, albeit reflecting a much higher contribution of extrinsic factors to cancer risk.

Mentions: According to the above hypothesis, both intrinsic and extrinsic factors can impart cancer risk through the accumulation of these errors, especially the ‘driver mutations’ (Arrow 3, Fig. 1). As such, a correlational analysis between cancer risk and cell division, for either stem or non-stem cells, is unable to differentiate between the contributions of intrinsic and extrinsic factors. This is best illustrated through a thought experiment where we consider a hypothetical scenario of a sudden emergence of a very potent mutagen globally such as a strong radiation burst from a nuclear fallout that quadruples the lifetime risks for all cancers. In this scenario, it transpires that the proportion of cancer risk explained by intrinsic random errors would be small (at most 1/4 even if we assume all the original risk was due to intrinsic processes). However, if we conduct regression analyses on either the new hypothetical cancer risks or the current cancer risks as reported, against the number of stem-cell divisions5, the correlations from both cases would be 0.81 (Fig. 2). This clearly argues against the implication that ~2/3 of variation could be explained by division-related random intrinsic errors and indicates that correlational analysis cannot distinguish between intrinsic and extrinsic factors.


Substantial contribution of extrinsic risk factors to cancer development.

Wu S, Powers S, Zhu W, Hannun YA - Nature (2015)

Correlation analysis of stem-cell division and cancer risk does not distinguish contribution of extrinsic vs. intrinsic factors to cancer riskThe black dots are data in Fig. 1 (also tabulated in Supplementary Table S1) of the original work by Tomasetti and Vogelstein5. The black line was their original regression line. The blue diamonds represent the hypothesized quadrupled cancer risks due to hypothetical exposure to an extrinsic factor such as radiation. The blue regression line for the hypothetical risk data maintains the same correlation as the original black line, albeit reflecting a much higher contribution of extrinsic factors to cancer risk.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4836858&req=5

Figure 2: Correlation analysis of stem-cell division and cancer risk does not distinguish contribution of extrinsic vs. intrinsic factors to cancer riskThe black dots are data in Fig. 1 (also tabulated in Supplementary Table S1) of the original work by Tomasetti and Vogelstein5. The black line was their original regression line. The blue diamonds represent the hypothesized quadrupled cancer risks due to hypothetical exposure to an extrinsic factor such as radiation. The blue regression line for the hypothetical risk data maintains the same correlation as the original black line, albeit reflecting a much higher contribution of extrinsic factors to cancer risk.
Mentions: According to the above hypothesis, both intrinsic and extrinsic factors can impart cancer risk through the accumulation of these errors, especially the ‘driver mutations’ (Arrow 3, Fig. 1). As such, a correlational analysis between cancer risk and cell division, for either stem or non-stem cells, is unable to differentiate between the contributions of intrinsic and extrinsic factors. This is best illustrated through a thought experiment where we consider a hypothetical scenario of a sudden emergence of a very potent mutagen globally such as a strong radiation burst from a nuclear fallout that quadruples the lifetime risks for all cancers. In this scenario, it transpires that the proportion of cancer risk explained by intrinsic random errors would be small (at most 1/4 even if we assume all the original risk was due to intrinsic processes). However, if we conduct regression analyses on either the new hypothetical cancer risks or the current cancer risks as reported, against the number of stem-cell divisions5, the correlations from both cases would be 0.81 (Fig. 2). This clearly argues against the implication that ~2/3 of variation could be explained by division-related random intrinsic errors and indicates that correlational analysis cannot distinguish between intrinsic and extrinsic factors.

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Applied Mathematics and Statistics, Stony Brook University, Stony Brook, New York 11794, USA.

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.

Show MeSH
Related in: MedlinePlus