Cancer, Stem Cells, and Bad Luck

written by Ted Schettler, MD, MPH
Science Director

Ted SchettlerThe new year got off to a fast start in cancer-related research with a paper published in the January 2nd issue of the prestigious journal Science titled “Variation in cancer risk among tissues can be explained by the number of stem cell divisions”, co-authored by C. Tomasetti and B. Vogelstein of Johns Hopkins University.  The authors “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 [stem cells] maintaining that tissue’s homeostasis.”

They based this conclusion on a comparison of lifetime risk of cancer in various tissues (expressed logarithmically) with an estimate of total lifetime stem cell divisions in those tissues for which there is some agreement about stem cell mass and dynamics. Breast and prostate cancers were not included because of lack of consensus around stem cell properties.

The paper says they included 31 tissue types, but actually it was fewer since the authors double counted lung, liver, head and neck, duodenum, and colorectal, each of which they evaluated with and without known links to cancer (smoking, hepatitis C virus, human papillomavirus, and familial adenomatous polyposis, respectively). For the tissues evaluated, the correlation between lifetime cancer risk and total number of stem cell divisions was quite strong. And, by separating smokers from non-smokers, the analysis clearly shows that lifetime lung cancer risk is much higher in smokers, assuming a similar number of lung stem cell divisions in the two groups. So far so good.

But, then the authors say, “A linear correlation equal to 0.804 suggests that 65% (39% to 81%; 95% CI) of the differences in cancer risk among different tissues can be explained by the total number of stem cell divisions in those tissues. Thus, the stochastic effects of DNA replication appear to be the major contributor to cancer in humans.” Now they have not only made the leap from correlation to causation but also decided that random mutations in dividing stem cells must be responsible, without seriously considering alternative explanations. There is no discussion of potential impacts of environmental agents, such as chemical mutagens or radiation, on DNA during stem cell division and only brief mention of the possibility that the total number of stem cells in an organ and their proliferation rate may be influenced by genetic and environmental factors.

Having concluded that random mutations in dividing stem cells must be the major contributor to cancer in humans, the authors say that most cancer variability among tissues is due to “bad luck” and in some cases, not much is preventable. Not surprisingly, the take-home message picked up by much of the press coverage is that most cancer—not cancer variability among tissues—but most cancer is due to “bad luck”. The authors have reinforced this message in press interviews.

The study and its press coverage have generated vigorous internet discussion, including on CHE’s Cancer and Environment listserv. Some commenters have criticized the journalists who failed to clearly describe what the study actually showed and just as importantly, what it did not show. Others have commented on the limited tissues in the study, the authors’ leap from correlation to causation, and their failure to consider explanations other than the bad luck of random mutations. Some cancer biologists note that the argument is based entirely on the somatic mutation theory of cancer and that a tissue-based theory would look at these data differently. Epidemiologists point out that for some of the cancers studied, where the authors minimize the importance of environmental contributors, we actually know quite a lot about agents that contribute to their incidence.

Identifying a correlation between the number of stem cell divisions and lifetime cancer risk in a various tissues may have some value. But, having established that, tissues with larger populations of dividing stem cells could be at higher risk of developing cancer for a number of reasons. Although “bad luck” associated with random mutations may explain some baseline cancer incidence, the data presented in this paper do not support a theory that these random mutations are the major contributor to cancer risk in humans. Cancer trends in specific tissues over decades make clear that environmental factors are deeply involved. By drawing conclusions that go beyond their data, the authors may deflect attention from the critical need to expand public health cancer prevention programs in our homes, communities, and workplaces. That would truly be an unfortunate outcome.

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5 thoughts on “Cancer, Stem Cells, and Bad Luck

  1. Thank you for this enlightening article. I have not yet read the paper but have read about it and have been wondering about potential liberties taken with the information. I find it hard to believe that most cases of cancer could possibly be due to “bad luck”. I just completed a residency in integrative oncology and have a strong interest in helping people reduce their risks of cancer.

  2. Brandon Kenney has published a related post on RegBlog that we refer our readers to: Cancer study’s claims about “bad luck” may undermine preventive regulation,

    An excerpt: “Reaching the correct scientific interpretation could hold implications for regulatory policy, say some experts. They warn that politicians and pundits may wield the study’s conclusions, and popular media’s interpretation of it, to support budget cuts in preventive programs ranging from the U.S. Environmental Protection Agency’s (EPA) clean air initiatives to local smoking ordinances.”

  3. Pingback: Cancer blame industry absolves industry’s real culprits | WORK CANCER HAZARDS

  4. Pingback: Top 10: 1st quarter 2015 | Our Health and Environment Blog

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