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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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Estimation of the proportion of lifetime cancer risk that is not due entirely to “bad luck” based on: (a). total tissue stem-cell divisions originally reported in Tomasetti and Vogelstein5, and (b). total tissue cell divisionsHere red dots are cancers used to compute the “intrinsic” risk linear regression lines (red dashed lines). Blue dots are cancers known to have substantial extrinsic risks from epidemiology studies. The numbers in parentheses are the estimated percentages of cancer risks due to factors other than intrinsic risks.
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Figure 3: Estimation of the proportion of lifetime cancer risk that is not due entirely to “bad luck” based on: (a). total tissue stem-cell divisions originally reported in Tomasetti and Vogelstein5, and (b). total tissue cell divisionsHere red dots are cancers used to compute the “intrinsic” risk linear regression lines (red dashed lines). Blue dots are cancers known to have substantial extrinsic risks from epidemiology studies. The numbers in parentheses are the estimated percentages of cancer risks due to factors other than intrinsic risks.

Mentions: The above conclusion then raises the question of what proportion of total cancer risk is due to extrinsic versus intrinsic factors. In a data-driven approach, we first re-examine the quantitative relationship between the observed lifetime cancer risk and the divisions of the normal tissue stem cells as reported5, with a distinct alternative method. Our rationale is that intrinsic risk, or indeed its upper bound, can be better estimated by the lowest boundary on the plots of cancer risk vs. total tissue stem-cell divisions (red line in Fig. 3a). In other words, intrinsic cancer risk should be determined by the cancer incidence for those cancers with the least risk in the entire group controlling for total stem cell divisions (red dots in Fig. 3a). The argument here is that cancers with the same stem-cell divisions should share the same base of intrinsic cancer risk (if the relationship is causal); if one or more cancers would feature a much higher cancer incidence, for example, lung cancer among smokers vs. non-smokers, then this most likely reflects additional (and probably extrinsic) risk factors (smoking in this case). One could argue that the low-incidence tumor types may have lower incidences because of additional genetic repair mechanisms that restrict evolving malignant cells from accumulating sufficient numbers of genetic alterations required to become fully tumorigenic; however, without more specific data on the operation of repair mechanisms, these could drive the risk up or down, depending on whether they are less or more efficient in any particular tissue. Since, according to our hypothesis, intrinsic risk from stem-cell divisions would define the lowest bound for a given number of stem-cell divisions, we define an “intrinsic” risk line for stem-cell divisions by regressing the smallest cancer risks on any given number of stem-cell divisions (red line, Fig. 3a). The “intrinsic” risk lines themselves are still likely overestimates for the intrinsic risk; however, we should suspect that any cancer risk above that line implies additional biologic determinants, based on which we can compute the percentage of cancer risk not explained by intrinsic “randomness”. As shown in Fig. 3a, most cancer types have very high excess risks relative to the “intrinsic” risk line, indicating large proportions of risks unaccounted by the intrinsic factors, typically larger than 90%. Moreover, these estimated excess risks are very robust – with plausible measurement errors added to the total stem-cell divisions, the resulting excess risks remain essentially intact (Extended Data Table 1).


Substantial contribution of extrinsic risk factors to cancer development.

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

Estimation of the proportion of lifetime cancer risk that is not due entirely to “bad luck” based on: (a). total tissue stem-cell divisions originally reported in Tomasetti and Vogelstein5, and (b). total tissue cell divisionsHere red dots are cancers used to compute the “intrinsic” risk linear regression lines (red dashed lines). Blue dots are cancers known to have substantial extrinsic risks from epidemiology studies. The numbers in parentheses are the estimated percentages of cancer risks due to factors other than intrinsic risks.
© Copyright Policy - permissions-link
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4836858&req=5

Figure 3: Estimation of the proportion of lifetime cancer risk that is not due entirely to “bad luck” based on: (a). total tissue stem-cell divisions originally reported in Tomasetti and Vogelstein5, and (b). total tissue cell divisionsHere red dots are cancers used to compute the “intrinsic” risk linear regression lines (red dashed lines). Blue dots are cancers known to have substantial extrinsic risks from epidemiology studies. The numbers in parentheses are the estimated percentages of cancer risks due to factors other than intrinsic risks.
Mentions: The above conclusion then raises the question of what proportion of total cancer risk is due to extrinsic versus intrinsic factors. In a data-driven approach, we first re-examine the quantitative relationship between the observed lifetime cancer risk and the divisions of the normal tissue stem cells as reported5, with a distinct alternative method. Our rationale is that intrinsic risk, or indeed its upper bound, can be better estimated by the lowest boundary on the plots of cancer risk vs. total tissue stem-cell divisions (red line in Fig. 3a). In other words, intrinsic cancer risk should be determined by the cancer incidence for those cancers with the least risk in the entire group controlling for total stem cell divisions (red dots in Fig. 3a). The argument here is that cancers with the same stem-cell divisions should share the same base of intrinsic cancer risk (if the relationship is causal); if one or more cancers would feature a much higher cancer incidence, for example, lung cancer among smokers vs. non-smokers, then this most likely reflects additional (and probably extrinsic) risk factors (smoking in this case). One could argue that the low-incidence tumor types may have lower incidences because of additional genetic repair mechanisms that restrict evolving malignant cells from accumulating sufficient numbers of genetic alterations required to become fully tumorigenic; however, without more specific data on the operation of repair mechanisms, these could drive the risk up or down, depending on whether they are less or more efficient in any particular tissue. Since, according to our hypothesis, intrinsic risk from stem-cell divisions would define the lowest bound for a given number of stem-cell divisions, we define an “intrinsic” risk line for stem-cell divisions by regressing the smallest cancer risks on any given number of stem-cell divisions (red line, Fig. 3a). The “intrinsic” risk lines themselves are still likely overestimates for the intrinsic risk; however, we should suspect that any cancer risk above that line implies additional biologic determinants, based on which we can compute the percentage of cancer risk not explained by intrinsic “randomness”. As shown in Fig. 3a, most cancer types have very high excess risks relative to the “intrinsic” risk line, indicating large proportions of risks unaccounted by the intrinsic factors, typically larger than 90%. Moreover, these estimated excess risks are very robust – with plausible measurement errors added to the total stem-cell divisions, the resulting excess risks remain essentially intact (Extended Data Table 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