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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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Intrinsic cancer risk modeling, Part 2/2: Schema of stem-cell divisions and driver gene mutations based on which the theoretical lifetime intrinsic risks (tLIR) for cancer due to k driver gene mutations are computed.Here every colored circle represents the mutation of a new driver gene in the given stem cell (yellow: first mutation; green: second mutation; red: third mutation). If the mutation of 3 designated driver genes would induce a cancerous stem cell (k = 3), then this diagram shows a cancer occurrence as the second stem cell in the last generation (generation n) has accumulated all 3 driver gene mutations.
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Figure 9: Intrinsic cancer risk modeling, Part 2/2: Schema of stem-cell divisions and driver gene mutations based on which the theoretical lifetime intrinsic risks (tLIR) for cancer due to k driver gene mutations are computed.Here every colored circle represents the mutation of a new driver gene in the given stem cell (yellow: first mutation; green: second mutation; red: third mutation). If the mutation of 3 designated driver genes would induce a cancerous stem cell (k = 3), then this diagram shows a cancer occurrence as the second stem cell in the last generation (generation n) has accumulated all 3 driver gene mutations.

Mentions: As mentioned afore, for stem cells in a specific tissue, we assume they undergo two phases of divisions (Extended Data Fig. 5): (1) a total of m symmetric divisions before full tissue development, and (2) a total of a asymmetric divisions for normal tissue turnovers. So in a fully developed tissue, there are a total of S = 2m stem cells. For each stem cell, its probability of possessing all k hits for cancer onset after n = m + a divisions is P(Xn = k), which can be calculated from the previous part. Therefore, the theoretical lifetime intrinsic risk (tLIR) of developing cancer, i.e., the probability of at least one stem cell containing k hits during its life time, can be expressed as: tLIR=1-[1-P(Xn=k)]S


Substantial contribution of extrinsic risk factors to cancer development.

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

Intrinsic cancer risk modeling, Part 2/2: Schema of stem-cell divisions and driver gene mutations based on which the theoretical lifetime intrinsic risks (tLIR) for cancer due to k driver gene mutations are computed.Here every colored circle represents the mutation of a new driver gene in the given stem cell (yellow: first mutation; green: second mutation; red: third mutation). If the mutation of 3 designated driver genes would induce a cancerous stem cell (k = 3), then this diagram shows a cancer occurrence as the second stem cell in the last generation (generation n) has accumulated all 3 driver gene mutations.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4836858&req=5

Figure 9: Intrinsic cancer risk modeling, Part 2/2: Schema of stem-cell divisions and driver gene mutations based on which the theoretical lifetime intrinsic risks (tLIR) for cancer due to k driver gene mutations are computed.Here every colored circle represents the mutation of a new driver gene in the given stem cell (yellow: first mutation; green: second mutation; red: third mutation). If the mutation of 3 designated driver genes would induce a cancerous stem cell (k = 3), then this diagram shows a cancer occurrence as the second stem cell in the last generation (generation n) has accumulated all 3 driver gene mutations.
Mentions: As mentioned afore, for stem cells in a specific tissue, we assume they undergo two phases of divisions (Extended Data Fig. 5): (1) a total of m symmetric divisions before full tissue development, and (2) a total of a asymmetric divisions for normal tissue turnovers. So in a fully developed tissue, there are a total of S = 2m stem cells. For each stem cell, its probability of possessing all k hits for cancer onset after n = m + a divisions is P(Xn = k), which can be calculated from the previous part. Therefore, the theoretical lifetime intrinsic risk (tLIR) of developing cancer, i.e., the probability of at least one stem cell containing k hits during its life time, can be expressed as: tLIR=1-[1-P(Xn=k)]S

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