Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 2015 Jan, 347:78

Substantial contribution of extrinsic risk factors to cancer development. Nature Medicine 2016 Jan, 529:43Peto’s paradox and human cancers. Phil. Trans. R. Soc. B 2015 Apr, 370: 20150104.

Bad Luck vs. Peto’s Paradox

Variation in cancer risk among tissues can be explained by the number of stem cell divisions

Science 2015 Jan, 347:78

Paper 1

Incidence and Lifetime Risk of Cancer

% C

ance

r-fre

e po

pula

tion

100%

Age

Age-specific risk

Accumulated risk in lifetime

Age-specific incidence

Variation in Lifetime Risks among Cancers

6.9% for lung, 1.08% for thyroid, 0.6% for brain and the rest of the nervous system, 0.003% for pelvic bone,0.00072% for laryngeal cartilage

Science 2015 Sep, 359:1438

Possible Causes

1. Environmental risk factors: smoking, alcohol use, UV light, or HPV, etc.

2. Inherited genetic variation: explaining 5-10% of cases.3. Stochastic effects associated with the lifetime number of

stem cell divisions within each tissue (in layman’s term, aging).

The “Bad Luck” Hypothesis

Spearman’s rho = 0.81 (P < 3.5 × 10-8)Pearson’s linear correlation = 0.804 (P < 5.15 × 10-8)→ explain 65% of difference

How to Explain Different Risks from the Same #TSCD?

(#TSCD)

Extra risk score (ERS) = lifetime risk x log10 (#TSCD)

High ERS Links to Environmental or Hereditary Risk Factors

D (deterministic) TumorR (replicative) Tumor

1. The contribution of the classic determinants (external environment and heredity) to R-tumors is minimal. Even for D-tumors, however, replicative effects (intrinsic processes) are essential, and environmental and hereditary effects simply add to them.

2. Cancer risk based on #SCD explains the difference in cancer incidences between organs and that between animals.

3. For nonhereditary D-tumors, both primary prevention (life style, exposure, etc) and secondary prevention (early detection) could make a major impact. For R-tumors, primary prevention measures are not likely to be as effective, and secondary prevention should be the major focus.

Conclusion: “Bad Luck” Is the Most Important Cause of Cancer

Substantial contribution of extrinsic risk factors to cancer development.

Nature Medicine 2016 Jan, 529:43

Paper 2

#TSCD Can Be Influenced by Both Intrinsic and Extrinsic Factors

“Bad Luck” Hypothesis Cannot Explain Changes in Cancer Incidences

Correlation Does Not Distinguish Contribution of Extrinsic versus Intrinsic Factors to Cancer Risk

Intrinsic Risk Can Be Better Estimated by the Lowest Boundary on the Plot of Lifetime Risk vs #TSCD

The higher #TSCD, the lower risk per SCD.

The higher #TSCD, the higher “extrinsic” risk.

Total Number of Tissue Cell Division (#TTCD) Also Correlates Significantly with Lifetime Risk

(#TTCD)

Epidemiological Evidence of Cancer Risk Proportions Attributed to Environmental Exposures

Science 2015 Sep, 359:1438

Extrinsic Mutational Signatures Distribute Widely in Cancers

Percentages of intrinsic versus extrinsic mutational signature (MS)

When assuming every cell can be transformed in the simulation using data of TSCD or TTCD, 2 hits are sufficient to cause cancer, which are inconsistent with current data.

Intrinsic Replicative Errors Are Impossibly Efficient to Cause Cancer in Simulation

1. Simple regression analysis cannot distinguish between intrinsic and extrinsic factors.

2. Four approaches (lower bound intrinsic risk line, epidemiological evidence, mutational signatures, modelling theoretical lifetime intrinsic risk) provide a consistent estimate of contribution of extrinsic factors of > 70–90% in most common cancer types.

3. Cancer risk due to intrinsic stem-cell mutation errors alone is low for almost all cancers that require over two mutations (lower than the relatively conservative estimate based on data alone).

Conclusion: Extrinsic Exposure Is Important Cause of Cancer

Peto’s paradox and human cancers Phil. Trans. R. Soc. B 2015 Apr, 370: 20150104.

Paper 3

Peto’s Paradox

http://www.instituteofcaninebiology.org/blog/do-dogs-have-more-cancer-than-other-mammals

Why the Slope of the Trend Line Is Not Equal to 1?

#Total Division per Stem Cell (d) and #Stem Cells (s) Correlate with Cancer Risk Independently

#TSCD = s(2+d)-d

Risk per Stem Cell Division Is Not the Same for All Tissues But Reversely Correlates with #TSCD

There Is More Tan One Way to Fit: One- and Two-Factor Models to Explain Lower Risk in Tissues of Higher #TSCD

“Intrinsic Risk” Saturates in Cancers with High #TSCD, but Extrinsic Factors Add Risk on the Top of it.

#TSCD Fully Explains Cancer Risk in Organ-Specific, Rather than Histology-Specific Manner

1. Variation in cancer risk is statistically explained by the independent effects of stem cell division rate (d) and stem cell number (s).

2. Different relative contributions of d and s to explain variation in risk of cancers significantly associated with mutagenic effects (e.g. certain cancers with high ERS).

3. The results suggest that variation in cancer risk across human tissues is analogous to Peto’s paradox. However, the inter-tissue relationship is not flat as in the interspecific comparison, but appears to be an increasing, saturating function.

4. Tissues with high levels of stem cell turnover, such as the lining of the small intestine, might have evolved especially powerful anti-cancer mechanisms.

5. Natural selection for cancer prevention is consistent with observations of occurrence at post-reproductive ages, yet maintaining the evolved protection mechanisms that reduce incidences at younger ages.

Conclusion: “Default Setting” of Cancer Risks Is Different Among Organs

#TSCD within natural selection pressure (average cancer risk)

Summary: Cancer Is an Disease of Accelerating Aging

T & V linear trend line“Peto’s” saturating trend curve

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