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

Abstract

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.

Enhanced inflammation and attenuated tumor suppressor pathways are associated with oncogene‐induced lung tumors in aged mice

“…Thus, the age dependence of cancer is likely driven in large measure by the statistical likelihood over time that a given set of complementary driver mutations occurs within a single normal cell that transforms it into a malignant cancer cell. Recently, the multistage carcinogenesis model has been further refined by Tomasetti & Vogelstein (2015) to show that lifetime risk of a cancer type correlates with total number of normal stem/progenitor cell divisions that maintain homeostasis within the tissue of origin. Two‐thirds of cancers were estimated to be caused by stochastic replication errors in self‐renewing cells within a tissue.…”

Metformin and soybean-derived bioactive molecules attenuate the expansion of stem cell-like epithelial subpopulation and confer apoptotic sensitivity in human colon cancer cells

“…According to the CSC hypothesis, a small population of normal stem cells requisite for maintaining tissue homeostasis/renewal can initiate a tumor upon acquiring one or more driver mutations (Chandler 2010). Moreover, a recent study (Tomasetti and Vogelstein 2015) has suggested that the lifetime risk of many different types of cancer is strongly correlated with the total number of divisions of these normal self-renewing cells, and that random mutations arising during DNA replication are likely causative for the emergence of CSC. Interestingly, among the different epithelial stem cells analyzed in that study, those derived from the colon were shown to undergo one of the highest numbers of cell divisions.…”

Integration of mechanistic and pharmacokinetic information to derive oral reference dose and margin‐of‐exposure values for hexavalent chromium

“…As with tumors, the incidence of diffuse epithelial hyperplasia was highest in the proximal SI (duodenum) and lowest in the distal intestine (ileum). Diffuse epithelial hyperplasia is a non‐neoplastic lesion that, under chronic wounding, can lead to increased stem cell proliferation, which can promote transformation and carcinogenesis (Cohen & Ellwein, 1990; Cohen, Gordon, Singh, Arce, & Nyska, 2010; Tomasetti & Vogelstein, 2015). Because Cr(VI) flux through intestinal sections well describes the tumor response in the SI, and hyperplasia is a critical preceding event to tumor formation, intestinal flux was used to model hyperplasia incidence from the NTP (2008) 2 year bioassay.…”