You eat healthy, exercise regularly, and avoid toxic substances. You even—so far as you know—have “good genes.” You should be protected against cancer, right? Well, you are, but you likely overestimate the degree of protection you enjoy.

That’s the sobering conclusion from a statistics-savvy review of the scientific literature. The review, undertaken by researchers at Johns Hopkins University, determined that the differences between cancer incidence rates in different tissues were largely attributable to one key factor: random mutations that occur among dividing stem cells. Stated more precisely, this factor is the cumulative total number of divisions of stem cells in a particular tissue during an average person’s lifetime.

“All cancers are caused by a combination of bad luck, the environment, and heredity, and we’ve created a model that may help quantify how much of these three factors contribute to cancer development,” said Bert Vogelstein, M.D., a professor at the Johns Hopkins University School of Medicine, an investigator at the Howard Hughes Medical Institute, and one of the study’s co-authors. “Cancer-free longevity in people exposed to cancer-causing agents, such as tobacco, is often attributed to their ‘good genes,’ but the truth is that most of them simply had good luck.”

Overall—among the 31 tissue types considered in the study—two thirds of adult cancer incidence can be explained primarily by bad luck. Still, Dr. Vogelstein cautioned that poor lifestyles can add to the bad luck factor in the development of cancer, particularly in tissues where the correlation between stem cell mutations and cancer incidence is less pronounced.

“If two thirds of cancer incidence across tissues is explained by random DNA mutations that occur when stem cells divide, then changing our lifestyle and habits will be a huge help in preventing certain cancers, but this may not be as effective for a variety of others,” added biomathematician Cristian Tomasetti, Ph.D., a professor at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health. “We should focus more resources on finding ways to detect such cancers at early, curable stages.”

Details of the study appeared January 1 in the journal Science, in an article entitled, “Variation in cancer risk among tissues can be explained by the number of stem cell divisions.”

“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,” wrote the authors. “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.”

The 0.81 correlation, which 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, holds over five orders of magnitude. At the extremes, colorectal cancers were associated with more stem cell divisions (and higher rates of cancer incidence) whereas osteosarcomas were associated with fewer stem cell divisions (and lower rates of cancer incidence).

This observation is no more than what a glance at a scatterplot may yield; however, closer views of the data are available in the Science article, where the authors classified the types of cancers they studied into two groups. Specifically, the authors statistically calculated which cancer types had an incidence predicted by the number of stem cell divisions and which had higher incidence. They found that 22 cancer types could be largely explained by the “bad luck” factor of random DNA mutations during cell division. The other nine cancer types had incidences higher than predicted by “bad luck” and were presumably due to a combination of bad luck plus environmental or inherited factors.

“We found that the types of cancer that had higher risk than predicted by the number of stem cell divisions were precisely the ones you’d expect, including lung cancer, which is linked to smoking; skin cancer, linked to sun exposure; and forms of cancers associated with hereditary syndromes,” noted Dr. Vogelstein. “This study shows that you can add to your risk of getting cancers by smoking or other poor lifestyle factors. However, many forms of cancer are due largely to the bad luck of acquiring a mutation in a cancer driver gene regardless of lifestyle and heredity factors. The best way to eradicate these cancers will be through early detection, when they are still curable by surgery.”

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