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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 1/2: Propagation diagram of driver gene mutation states between generations in one stem cell based on which the stem cell mutation transition probabilities from one generation to the next are computed.
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Figure 8: Intrinsic cancer risk modeling, Part 1/2: Propagation diagram of driver gene mutation states between generations in one stem cell based on which the stem cell mutation transition probabilities from one generation to the next are computed.

Mentions: Based on the theory of the clonal stem-cell origin of cancer, in a given tissue, the stem cell would first go through m rounds of symmetric divisions (for each division, each stem cell would divide into two daughter stem cells) to reach a total of S stem cells (S = 2m) at the steady state. Subsequently, these S stem cells would go through a rounds of asymmetric divisions (for each division, each stem cell would yield only one daughter stem cell) throughout the lifetime of the tissue. This means the total number of lifetime stem cell divisions/generations is: n = m + a. Information on the total number of symmetric and asymmetric divisions as well as the total number of stem cells in steady state for various tissues discussed in this work has been extracted from Table S1 of the supplementary materials in Tomasetti and Vogelstein5. With k hits (mutations of k predetermined driver genes) on a stem cell required for cancer onset, the number of possible cell state at a given (stem cell) generation would be k +1, including a zero state with no hit. If we assume that once a hit occurs, it cannot be reversed and therefore be carried to all progeny cells, then a cell state may only transit from lower to higher or equal levels from generation to generation. In the Extended Data Fig. 4, we demonstrate with k = 3 the state transitions of accumulating driver gene mutations. Let Xg denote the number of driver mutations accumulated at generation g and r be the intrinsic driver gene mutation rate due to random errors during DNA replication, the transition probabilities from generation g to g + 1 for all possible states (0 ≤ i ≤ k) are derived as follows: P(Xg+1=i)=∑j=0iP(Xg+1=i∣Xg=j)P(Xg=j)=∑j=0i(k-ji-j)ri-j(1-r)k-iP(Xg=j)


Substantial contribution of extrinsic risk factors to cancer development.

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

Intrinsic cancer risk modeling, Part 1/2: Propagation diagram of driver gene mutation states between generations in one stem cell based on which the stem cell mutation transition probabilities from one generation to the next are computed.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

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

Figure 8: Intrinsic cancer risk modeling, Part 1/2: Propagation diagram of driver gene mutation states between generations in one stem cell based on which the stem cell mutation transition probabilities from one generation to the next are computed.
Mentions: Based on the theory of the clonal stem-cell origin of cancer, in a given tissue, the stem cell would first go through m rounds of symmetric divisions (for each division, each stem cell would divide into two daughter stem cells) to reach a total of S stem cells (S = 2m) at the steady state. Subsequently, these S stem cells would go through a rounds of asymmetric divisions (for each division, each stem cell would yield only one daughter stem cell) throughout the lifetime of the tissue. This means the total number of lifetime stem cell divisions/generations is: n = m + a. Information on the total number of symmetric and asymmetric divisions as well as the total number of stem cells in steady state for various tissues discussed in this work has been extracted from Table S1 of the supplementary materials in Tomasetti and Vogelstein5. With k hits (mutations of k predetermined driver genes) on a stem cell required for cancer onset, the number of possible cell state at a given (stem cell) generation would be k +1, including a zero state with no hit. If we assume that once a hit occurs, it cannot be reversed and therefore be carried to all progeny cells, then a cell state may only transit from lower to higher or equal levels from generation to generation. In the Extended Data Fig. 4, we demonstrate with k = 3 the state transitions of accumulating driver gene mutations. Let Xg denote the number of driver mutations accumulated at generation g and r be the intrinsic driver gene mutation rate due to random errors during DNA replication, the transition probabilities from generation g to g + 1 for all possible states (0 ≤ i ≤ k) are derived as follows: P(Xg+1=i)=∑j=0iP(Xg+1=i∣Xg=j)P(Xg=j)=∑j=0i(k-ji-j)ri-j(1-r)k-iP(Xg=j)

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