Which made perfect sense. When a cell divides, it has to duplicate all of its DNA. Every time this happens, it picks up a few mutations—typos, created when DNA is copied imperfectly. Most of these mutations are harmless, but some will disrupt crucial genes. And if stem cells collect enough mutations in the wrong genes, they start dividing uncontrollably, creating a tumor. So tissues whose stem cells divide more frequently should indeed be more susceptible to cancer.
That would have been completely uncontroversial, had Tomasetti and Vogelstein not framed their results in terms of “bad luck.” Some cancer-causing mutations are inherited, while others are inflicted upon our DNA by environmental risks like tobacco, sunlight, alcohol, or asbestos. Tomasetti and Vogelstein argued that the random mutations arising in dividing stem cells represent a third group—distinct from the other two, more important, and unlikely to be preventable. When they published their results in the journal Science, they wrote:
“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.”
The paper triggered a hailstorm of criticism. Some scientists chastised the methods. Why did they ignore common cancers like breast and prostate? Why did they only focus on the U.S.? Others accused the duo of undermining public health. Many personal choices, from quitting smoking to staying lean, can dramatically reduce one’s risk of cancers, but why would you bother if you read headlines saying that these diseases are “largely down to bad luck?”
Such headlines were disastrously wrong. For a start, Tomasetti and Vogelstein looked at the differences between body parts, not people. Their data explained why tumors are more likely to strike the bowel than the brain, but not this bowel versus that one. As oncologist Vinay Prasad tweeted: “[Their] paper does not explain to cancer patients why they got cancer. [It] explains why cancer doctors get more colon cancer consults than sarcoma consults.”
Last week, the controversial duo returned with another co-author and a second paper, which provides more data for their “bad-luck hypothesis.” This time, they looked at 17 cancers, including breast and prostate. They also went beyond the U.S., collating data from 69 countries that vary greatly in their cancer rates and their exposure to environmental risks. And despite that variation, everywhere the team looked, they found the same strong correlation between a tissue’s cancer risk and its rate of stem cell divisions.
Next, they used data from tumor-sequencing projects and epidemiological studies to sort cancer-causing mutations into three buckets, depending on their origin. Overall, they calculated that 66 percent of cancer mutations are due to random, unavoidable replication errors (R), 29 percent are due to environmental factors (E), and 5 percent are inherited (H). But those proportions vary a lot between cancers: in lung cancer, just 35 percent of mutations are randomly acquired, compared to 77 percent for pancreatic cancer.