According to a new study funded by the National Institutes of Health and published by Johns Hopkins University researchers, the majority of human cancers may be caused by the random genetic mutations that arise from normal DNA replication. Put more bluntly, the research suggests that the “bad luck” of random mutations plays a predominant role in causing a majority of cancers. The article, “Variation in cancer risk among tissues can be explained by the number of stem cell divisions,” was published in the 2 January 2015 edition of Science. The study has caused quite a stir (see e.g., NY Times, CBS News, and 2020 Science blog) by suggesting that the majority of cancers are caused by normal cellular processes and cannot necessarily be “blamed” on something, or someone. The reaction to the study and its press release prompted a clarification from the authors.
The study, underwritten by four National Institutes of Health grants and three nonprofit cancer foundations, acknowledges that it has long been understood that heredity and environmental factors can cause some types of cancers in some individuals, but raised the question of whether all cancers are caused by those two factors. The authors, Cristian Tomasetti and Bert Vogelstein, set out to investigate a third possible category of cancer causation based on the concept that many genetic alterations occur simply by chance during normal DNA replication. This third category is the stochastic effects associated with the lifetime number of stem cell divisions.
“That cancer is largely the result of acquired genetic and epigenetic changes is based on the somatic mutation theory of cancer,” the authors note “and has been solidified by genome-wide analyses.” The researchers predicted that, because endogenous mutation rates for all human cell types are nearly identical, there should be a strong correlation between the lifetime number of divisions among the stem cells within each organ (the only cells that can self-renew and are responsible for the tissue’s architecture), and the lifetime risk of cancer in that organ. In other words, if random mutations from normal cellular division is responsible for causing cancer, you should see more cancers in organs where stem cells divide more frequently.
[A] strong correlation between the lifetime number of divisions among the stem cells . . . and the lifetime risk of cancer in that organ.
The researchers identified 31 tissue types for which stem cell data could be quantitively assessed and plotted the data to compare the total number of stem cell division in a lifetime, to the lifetime risk for cancers in those organs. The result was extraordinary. There was a clear, steep, linear pattern – – the more stem cell divisions the higher the lifetime risk of getting cancer in that organ. “The correlation between these two very different parameters – number of stem cell divisions and lifetime risk – was striking, with a highly positive correlation.” In fact, the correlation extended across five orders of magnitude, and applied “to cancers with enormous differences in incidence.”
Tomasetti and Vogelstein checked their findings against the other causative factors of environmental and heredity-induced mutations. If their theory was correct, the authors expected to see more cancer in organs with more stem cell divisions and known increased risk from environmental or inherited causes. “[I]f there is a high cancer risk of that tissue type relative to its number of stem cell divisions – then one would expect that environmental or inherited factors would play a higher role in that cancer’s risk.”
That is exactly what they found.
The authors conclude that their analysis “shows that stochastic effects associated with DNA replication contribute in a substantial way to human cancer incidence in the United States.” The implications of this study extend beyond public health (diagnosis, treatment, and prevention) to scientific and medical research, as well as product liability and toxic tort litigation.
For more, see www.sciencemag.org/content/347/6217/78/suppl/DC1