In 2015, a study claimed that "bad luck" was the cause of cancer, more so than environmental factors or inherited genes; implying that preventive measures such as environmental cleanups, smoking cessation and diet changes were pointless.

It sparked a huge debate on whether the authors were paid off by the chemical industry to create a "massive" stunt that was "hidden behind fancy numbers of doubtful quality."

But this week, the same authors published another paper that reinforces their original finding, and also corrects the widespread misinterpretations of it. The study looked at health records from 69 countries and concluded that two-thirds of cancer-causing genetic mutations arise from "bad luck" of a healthy dividing cell making a random mistake when it replicates DNA.

Treading carefully, the researchers explained that this did not mean 66% of cancers cannot be prevented; rather, the understanding of the role of the errors by mere probability 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 2015 and 2017 studies.

"This is particularly true for parents of children who have cancer" and might blame the disease on hereditary or environmental factors, he added.

Rates of cancer in different tissues due to different rates of cell division

Both studies compared the rates of cancer in different tissues with those of the rate of healthy cells in those tissues divide - and found a very close correlation. Cells of the large intestine divide frequently and 5% of the population develop cancer in that tissue. Cells of the small intestine on the other hand, rarely divide, and only 0.2% develop cancer in those tissues.

The Hopkins team based their theory on the fact that dividing cells do not replicate DNA perfectly and every division presents an opportunity for a cancer-causing mutation to arise. In the latest study, two-thirds of the differences in cancer rates across all tissues are due to the differences in the rates of cell division in those tissues. This result reproduces the results of their previous US-only study.

As such, the cause of many cancers might still be environmental factors - with at least 60% of mutations in skin and lung cancer due to the environment, compared with 15% or less in prostate, bone, brain and breast cancers. But the difference in cancer rates in different tissues can still be due to the different underlying rates of cell division, according to the researchers.

They also concluded that while replication mistakes were responsible for 66% of the mutations, 29% were due to environmental factors and 5% are due to heredity.

Clearing widespread misinterpretations of the first paper

In a noble move, the scientists also corrected themselves for claiming that cancer was caused by "bad luck" in their previous study. This time, the Hopkins team agree that there is a difference between how cancer-causing mutations come about and whether or not, that cancer is preventable.

For instance, 65% of mutations in lung cancers are by chance, but 89% of those cancers are preventable by avoiding smoking as several mutations - due to the environment and by chance - are required for cancer. As such, the new study resolves the conflict between biological mechanisms and population-level estimates of how big of a role prevention measures play.

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

Meeting in the middle

But not all critics of the first paper were convinced. Their critics still hold that the environment's effect on cancer goes beyond mutations as whether a few malignant cells actually generate a dangerous tumour depends on multiple factors such as levels of inflammation, insulin and obesity. The Hopkins researchers did not look into this.

"I am not very impressed with the overall conclusion," said Dr Yusuf Hannun, director of the Stony Brook Cancer Centre, who led a separate 2015 study claiming that the vast majority of cancers are due to extrinsic factors, not random mistakes in DNA replicating.

But all in all, the debate certainly underscores how it is almost never possible to be certain about what causes an individual tumour, and the fact that as much as cancer risk can be reduced by changing lifestyle choices, chance still plays a significant role. MIMS

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