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

By C. Tomasetti, Bert Vogelstein. Science, 2015

1,504 citations recorded by the source corpus.

Crunching the numbers to explain cancer Why do some tissues give rise to cancer in humans a million times more frequently than others? Tomasetti and Vogelstein conclude that these differences can be explained by the number of stem cell divisions. By plotting the lifetime incidence of various cancers against the estimated number of normal stem cell divisions in the corresponding tissues over a lifetime, they found a strong correlation extending over five orders of magnitude. This suggests that random errors occurring during DNA replication in normal stem cells are a major contributing factor in cancer development. Remarkably, this “bad luck” component explains a far greater number of cancers than do hereditary and environmental factors. Science, this issue p. 78 Errors arising by chance during normal stem cell division explain more cancers than do hereditary or environmental factors. 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.

Subfields: Cancer Research, Genetics, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/c7de92ea0f8ddfeec38d3a21500a917cd388343d

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Citations in the corpus

Revisiting the hallmarks of cancer. (2017, neutral): “In one of the most critically acclaimed cancer papers of the modern times [212].”
Immunity, inflammation, and cancer: an eternal fight between good and evil. (2015, neutral): “Such findings and others counter the recent suggestion that cancer rates and risks are purely dictated by the number of cancer-initiating cell divisions (42).”
Pan-cancer analysis of whole genomes (2020, methodology): “In support of this, we found an inverse correlation between previously estimated rates of stem cell division across tissues 82 and the frequency of telomere maintenance abnormalities ( P = 0.01, Poisson regression) (Extended Data Fig.”
Intratumor heterogeneity: the Rosetta stone of therapy resistance (2020, background): “Whereas the sufficiency of these baseline replication error rates to account for carcinogenesis remains a subject of debate (Beckman and Loeb, 2006; Tomasetti and Vogelstein, 2015; Tomlinson et al., 1996), many tumors display increased mutation rates, due to either increased external or internal…”
Cholangiocarcinoma 2020: the next horizon in mechanisms and management (2020, background): “Small bile duct and cholangiolocarcinoma iCCA usually develop on a background of chronic liver disease (such as chronic viral hepatitis and cirrhosis) 38,46,70 , characterized by HpSC activation 71,73,74 .”
Neuronal activity-dependent control of postnatal neurogenesis and gliogenesis (2018, neutral): “…retaining a dedicated stem cell population requires extra energy and resources, and when they acquire oncogenic mutations over time, these proliferative cells can become tumorigenic (Alcantara Llaguno et al. 2009), leading to harmful sequelae to the host tissue (Tomasetti & Vogelstein 2015).”