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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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A schematic view of how intrinsic processes and extrinsic factors are related to cancer risks through stem-cell divisionThis hypothesis maintains the strong role of stem-cell division in imparting cancer risk, but it also illustrates the potential contributions of both intrinsic and extrinsic factors, both operating through stem-cell division. Other effects, e.g. through division of non-stem cells, are not considered here.
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Figure 1: A schematic view of how intrinsic processes and extrinsic factors are related to cancer risks through stem-cell divisionThis hypothesis maintains the strong role of stem-cell division in imparting cancer risk, but it also illustrates the potential contributions of both intrinsic and extrinsic factors, both operating through stem-cell division. Other effects, e.g. through division of non-stem cells, are not considered here.

Mentions: We start by making the conservative and yet conventional assumption that errors occurring during the division of cells, being routes of malignant transformation, can be influenced by both intrinsic processes as well as extrinsic factors (Fig. 1). “Intrinsic processes” include those that result in mutations due to random errors in DNA replication whereas “extrinsic factors” are environmental factors that affect mutagenesis rates (such as UV radiation, ionizing radiation, and carcinogens). For example, radiation can cause DNA damage, which would primarily result in deleterious mutations with functional consequences on cancer development only after cell division. Therefore, extrinsic factors may act through the accumulation of genetic alterations during cell division to increase cancer risk. Accordingly, intrinsic risk would result from those apparently uncontrollable intrinsic processes (Arrow 1, Fig. 1) as well as from those highly modifiable and thus preventable extrinsic factors (Arrow 2, Fig. 1).


Substantial contribution of extrinsic risk factors to cancer development.

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

A schematic view of how intrinsic processes and extrinsic factors are related to cancer risks through stem-cell divisionThis hypothesis maintains the strong role of stem-cell division in imparting cancer risk, but it also illustrates the potential contributions of both intrinsic and extrinsic factors, both operating through stem-cell division. Other effects, e.g. through division of non-stem cells, are not considered here.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

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

Figure 1: A schematic view of how intrinsic processes and extrinsic factors are related to cancer risks through stem-cell divisionThis hypothesis maintains the strong role of stem-cell division in imparting cancer risk, but it also illustrates the potential contributions of both intrinsic and extrinsic factors, both operating through stem-cell division. Other effects, e.g. through division of non-stem cells, are not considered here.
Mentions: We start by making the conservative and yet conventional assumption that errors occurring during the division of cells, being routes of malignant transformation, can be influenced by both intrinsic processes as well as extrinsic factors (Fig. 1). “Intrinsic processes” include those that result in mutations due to random errors in DNA replication whereas “extrinsic factors” are environmental factors that affect mutagenesis rates (such as UV radiation, ionizing radiation, and carcinogens). For example, radiation can cause DNA damage, which would primarily result in deleterious mutations with functional consequences on cancer development only after cell division. Therefore, extrinsic factors may act through the accumulation of genetic alterations during cell division to increase cancer risk. Accordingly, intrinsic risk would result from those apparently uncontrollable intrinsic processes (Arrow 1, Fig. 1) as well as from those highly modifiable and thus preventable extrinsic factors (Arrow 2, Fig. 1).

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