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t was the study that launched hundreds of scientific rebuttals, insinuations that the authors had been paid off by the chemical industry, and charges that it was a “massive” stunt “hidden behind fancy numbers of doubtful quality.”

The claim that sparked this controversy? That “bad luck,” more than environmental factors or inherited genes, affects whether someone develops cancer, implying that preventive efforts from smoking cessation to environmental cleanups were largely pointless.

Now the authors of that 2015 paper are back. In a study published on Thursday in Science, they double down on their original finding but also labor mightily to correct widespread misinterpretations of it. This time, using health records from 69 countries, they conclude that 66 percent of cancer-causing genetic mutations arise from the “bad luck” of a healthy, dividing cell making a random mistake when it copies its DNA.

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The scientists go to great pains to explain that this doesn’t mean that two-thirds of cancers are beyond the reach of prevention. But understanding the role of these unforced errors “could provide comfort to the millions of patients who developed cancer but led near-perfect [healthy] lifestyles,” said cancer biologist Dr. Bert Vogelstein of Johns Hopkins University, senior author of both the original study and the new one. “This is particularly true for parents of children who have cancer” and might blame the tragedy on the genes they passed on to their child or the environment they provided, he said.

“They did it right this time,” Dr. Otis Brawley, chief medical officer of the American Cancer Society, said of the authors. “In the first paper they upset a lot of people who are advocates for cancer prevention, and confused a lot of people,” by leaving the impression that most cancers are beyond the reach of prevention. “But a reasonable person can read this one and think, prevention is not useless.”

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Separate research has shown that roughly 42 percent of cancers are preventable by, for instance, not smoking, maintaining a healthy weight, and not being exposed to cancer-causing pollutants.

Not all critics of the first paper were swayed, however. “I am not very impressed with the overall conclusion,” said Dr. Yusuf Hannun, director of the Stony Brook Cancer Center, who led a 2015 study showing that the vast majority of cancers are due to extrinsic factors, not random mistakes in DNA copying.

The original “bad luck” study as well as this one compared how rates of cancer in different tissues relate to the frequency with which healthy cells in those tissues — lung, bone, brain, and more — divide.

They found a very close correlation. Cells of the large intestine divide frequently, and 5 percent of people develop cancer in that tissue. Cells of the small intestine divide rarely, and only 0.2 percent of people develop cancer there. Because dividing cells do not always copy their DNA perfectly, every division is an opportunity for a cancer-causing mutation to arise; more divisions, more cancers, the Hopkins team argued.

Overall, they found, about two-thirds of the difference in cancer rates from one kind of tissue to another is due to differences in the rates of cell division in those tissues. That conclusion echoes the one in their previous, US-only study, and held for all 17 cancer types and all 69 countries they analyzed.

That doesn’t mean that two-thirds of cancers are caused by unforced errors in DNA copying, however. The high or low rate of cell divisions account for two-thirds of the differences in cancer rates from one kind of tissue to another. For instance, the “cause” of the Himalayas is the Indian tectonic plate smashing into the Eurasian Plate. That has produced more than a dozen peaks reaching above 26,000 feet. But the difference between K2’s 28,251 feet and Annapurna’s 26,545 feet is nevertheless partly due to random factors, from wind erosion to the angle of the rock strata underlying each mountain.

Similarly, the cause of many cancers might be environmental factors. But the difference in cancer rates in different tissues can still be the result of different underlying rates of cell division. That’s what the Hopkins scientists found.

A key advance in the new paper is its analysis of cancer genomes in a United Kingdom database to classify where cancer-causing mutations came from: the environment, heredity, or those random DNA-copying mistakes. “This is the first time someone has looked at the proportions of mutations in cancer and assigned them” to one of these categories, said Hopkins mathematician Cristian Tomasetti.

After a roundabout calculation, the researchers concluded that DNA-copying mistakes are responsible for 66 percent of the mutations, while 29 percent are due to environmental factors and 5 percent to heredity. Different cancers differ significantly: At least 60 percent of mutations triggering skin and lung cancer are due to the environment, they calculate, compared with 15 percent or less in prostate, bone, brain, and breast cancers.

The scientists stirred controversy last time for an inference they drew from the “bad luck” finding. If so many cancers arise from mistakes that cells make when they divide, then reducing exposure to cancer-causing compounds such as those in cigarettes or workplace carcinogens won’t help much, they argued.

But that does not follow, other cancer experts said. Several mutations are required for cancer. Therefore, if two out of three required mutations arise from copying mistakes, but the third comes from an environmental carcinogen, then avoiding that carcinogen prevents the cancer.

This time the Hopkins team agrees. There is a difference between how cancer-causing mutations come about and whether that cancer is preventable, they acknowledge. For instance, 65 percent of mutations in lung cancers arose randomly but 89 percent of those cancers are preventable by avoiding smoking, Tomasetti said.

Their critics argue that the environment’s effect on cancer goes beyond mutations, in which case prevention might have an even bigger role to play. Whether a few malignant cells form a dangerous tumor depends on, among other things, levels of inflammation, insulin, and obesity. Those influences don’t show up in genomic analyses like those the Hopkins researchers did but are affected by lifestyle and environmental factors, said Ross Prentice, a renowned cancer biostatistician at Fred Hutchinson Cancer Center in Seattle.

“Environmental exposures can influence cancer risk in many ways,” he said, including whether cells repair cancer-causing mutations and whether the immune system destroys tumor cells before they cause actual disease.

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  • A simplified model and a little math: most cancers involve multiple mutations, so the fact that only about 30% of a particular cancer causing mutation are because of environmental factors does not mean that 30% of those cancers are avoidable.

    Consider a mutation that naturally occurs in 2 per 1000 of cell replications, and an environmental factor that causes mutations in an additional 1 per 1000. (So 2/3’s are natural replication errors and 1/3 are environmental). Without the environmental factor, about (2/1000)^2 = 4 per million cells will have 2 mutations, but with the environmental factor, (2/1000 + 1/1000)^2 = 9 per million cells, a little more than twice as many.

    Consequently, only 1/3 of these cancer mutations are environmental, but more than 1/2 the cancers are preventable.

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