Cancer etiology. 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.

Fig. 1. The relationship between the number of stem cell divisions in the lifetime of a given tissue and the lifetime risk of cancer in that tissue

Values are from table S1, the derivation of which is discussed in the supplementary materials.

Fig. 2. Stochastic (replicative) factors versus environmental and inherited factors: R-tumor versus D-tumor classification

The adjusted ERS (aERS) is indicated next to the name of each cancer type. R-tumors (green) have negative aERS and appear to be mainly due to stochastic effects associated with DNA replication of the tissues' stem cells, whereas D-tumors (blue) have positive aERS. Importantly, although the aERS was calculated without any knowledge of the influence of environmental or inherited factors, tumors with high aERS proved to be precisely those known to be associated with these factors. For details of the derivation of aERS, see the supplementary materials.