scholarly journals Determining cancer risk: the evolutionary multistage model or total stem cell divisions?

2020 ◽  
Vol 287 (1941) ◽  
pp. 20202291
Author(s):  
Leonard Nunney ◽  
Kevin Thai
Keyword(s):  
Stem Cell ◽  
Cancer Risk ◽  
Cancer Incidence ◽  
Evolutionary Model ◽  
Multistage Model ◽  
Incidence Data ◽  
Cell Divisions ◽  
Darwinian Fitness ◽  
Stem Cell Divisions ◽  
Cancer Suppression

A recent hypothesis proposed that the total number of stem cell divisions in a tissue (TSCD model) determine its intrinsic cancer risk; however, a different model—the multistage model—has long been used to understand how cancer originates. Identifying the correct model has important implications for interpreting the frequency of cancers. Using worldwide cancer incidence data, we applied three tests to the TSCD model and an evolutionary multistage model of carcinogenesis (EMMC), a model in which cancer suppression is recognized as an evolving trait, with natural selection acting to suppress cancers causing a significant mean loss of Darwinian fitness. Each test supported the EMMC but contradicted the TSCD model. This outcome undermines results based on the TSCD model quantifying the relative importance of ‘bad luck' (the random accumulation of somatic mutations) versus environmental and genetic factors in determining cancer incidence. Our testing supported the EMMC prediction that cancers of large rapidly dividing tissues predominate late in life. Another important prediction is that an indicator of recent oncogenic environmental change is an unusually high mean fitness loss due to cancer, rather than a high lifetime incidence. The evolutionary model also predicts that large and/or long-lived animals have evolved mechanisms of cancer suppression that may be of value in preventing or controlling human cancers.

scholarly journals Cancer Etiology: Variation in Cancer Risk among Tissues is Poorly Explained by the Number of Gene Mutations

2017 ◽  
Author(s):  
Miguel Lopez-Lazaro
Keyword(s):  
Stem Cell ◽  
Cancer Risk ◽  
Gene Mutations ◽  
Cancer Registries ◽  
Cancer Etiology ◽  
Driver Genes ◽  
Incidence Data ◽  
Cell Divisions ◽  
Stem Cell Divisions ◽  
Risk Of Cancer

Recent evidence indicates that the risk of being diagnosed with cancer in a tissue is strongly correlated (0.80) with the number of stem cell divisions accumulated by the tissue. Since cell division can generate random mutations during DNA replication, this correlation has been used to propose that cancer is largely caused by the accumulation of unavoidable mutations in driver genes. However, no correlation between the number of gene mutations and cancer risk across tissues has been reported. Because many somatic mutations in cancers originate prior to tumor initiation and the number of cell divisions occurring during tumor growth is similar among tissues, here I use whole genome sequencing information from 22,086 cancer samples and incidence data from the largest cancer registry in each continent to study the relationship between the number of gene mutations and the risk of cancer across 33 tissue types. Results show a weak positive correlation (mean = 0.14) between these two parameters in each of the five cancer registries. The correlation became stronger (mean = 0.50) when gender-related cancers were excluded. Results also show that 1,003 samples from 29 cancer types have zero mutations in genes. These data suggest that cancer etiology can be better explained by the accumulation of stem cell divisions than by the accumulation of gene mutations. Possible mechanisms by which the accumulation of cell divisions in stem cells increases the risk of cancer are discussed.

scholarly journals Peto's paradox and human cancers

2015 ◽  
Vol 370 (1673) ◽  
pp. 20150104 ◽  
Author(s):  
Robert Noble ◽  
Oliver Kaltz ◽  
Michael E. Hochberg
Keyword(s):  
Stem Cell ◽  
Natural Selection ◽  
Cancer Risk ◽  
Cancer Incidence ◽  
Human Cancer ◽  
Independent Effect ◽  
Anatomical Site ◽  
Lifetime Cancer Risk ◽  
Cell Divisions ◽  
Stem Cell Divisions

Peto's paradox is the lack of the expected trend in cancer incidence as a function of body size and lifespan across species. The leading hypothesis to explain this pattern is natural selection for differential cancer prevention in larger, longer lived species. We evaluate whether a similar effect exists within species, specifically humans. We begin by reanalysing a recently published dataset to separate the effects of stem cell number and replication rate, and show that each has an independent effect on cancer risk. When considering the lifetime number of stem cell divisions in an extended dataset, and removing cases associated with other diseases or carcinogens, we find that lifetime cancer risk per tissue saturates at approximately 0.3–1.3% for the types considered. We further demonstrate that grouping by anatomical site explains most of the remaining variation. Our results indicate that cancer risk depends not only on the number of stem cell divisions but varies enormously (approx. 10 000 times) depending on anatomical site. We conclude that variation in risk of human cancer types is analogous to the paradoxical lack of variation in cancer incidence among animal species and may likewise be understood as a result of evolution by natural selection.

Role of stem-cell divisions in cancer risk

Nature ◽  
2017 ◽  
Vol 548 (7666) ◽  
pp. E13-E14 ◽  
Author(s):  
Cristian Tomasetti ◽  
Rick Durrett ◽  
Marek Kimmel ◽  
Amaury Lambert ◽  
Giovanni Parmigiani ◽  
...  
Keyword(s):  
Stem Cell ◽  
Cancer Risk ◽  
Cell Divisions ◽  
Stem Cell Divisions

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

Science ◽  
2015 ◽  
Vol 347 (6217) ◽  
pp. 78-81 ◽  
Author(s):  
Cristian Tomasetti ◽  
Bert Vogelstein
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Dna Replication ◽  
Environmental Factors ◽  
Cancer Risk ◽  
Strongly Correlated ◽  
Cell Divisions ◽  
Human Cancers ◽  
Different Types ◽  
Stem Cell Divisions

Some tissue types give rise to human cancers millions of times more often than other tissue types. Although this has been recognized for more than a century, it has never been explained. Here, we show that the lifetime risk of cancers of many different types is strongly correlated (0.81) with the total number of divisions of the normal self-renewing cells maintaining that tissue’s homeostasis. These results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.

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