What causes cancer? High-profile culprits obviously include bum genes inherited from parents and harmful environmental and lifestyle factors, such as smoking or not wearing sunscreen. But in a new study in Science, researchers yet again say a big factor is random mutations—those that naturally and unavoidably occur as our error-prone cells go about the normal process of replication.

In fact, two-thirds of the mutations behind cancer are random—not inherited or induced by our environment—researchers at Johns Hopkins conclude from a fresh statistical analysis. But, they caution, the contribution of genetic bad luck doesn’t mean that many cancers aren’t preventable. It’s a point they emphasize carefully after their previous work set off fiery controversy on the matter.

Back in early 2015, the lead researchers of the new study, Cristian Tomasetti and Bert Vogelstein, published a straightforward hypothesis (also in Science) that the risk of cancers can, in part, be explained by simple stem cell replication. The idea being that the more stem cells a tissue type has and the faster those cells make copies of themselves, the more chances there are for mutations from sheer cellular sloppiness—thus, more chances for cancer. So, if a tissue type has a lot of fast-replicating stem cells, it would have a higher risk of developing cancer over a person's lifetime. This could help explain why different tissue types do have different risks of cancer. Lung and thyroid cancer are far more common than brain and pelvic bone cancer, for instance.

In an analysis of cancer risks, the hypothesis held up. The researchers compared different lifetime risks that Americans have of getting cancer in 25 different tissues. They concluded that: “65 percent of the differences in cancer risk among different tissues can be explained by the total number of stem cell divisions in those tissues.”

It was an interesting finding to be sure, but it got twisted. News headlines ran as: “Two-thirds of adult cancers largely ‘down to bad luck’ rather than genes” and “Most cancer types 'just bad luck'.”

The misinterpretations sparked a blast of corrective pieces, opinions, and even new studies. The authors helped with new explainer pieces. Health experts and doctors publicly fretted that people would start ignoring solid health advice—like "wear sunscreen" and "don’t smoke"—if they thought that their chances of getting cancer were just random anyway.

Evolving discussion

With the new study, Tomasetti, Vogelstein, and colleague Lu Li essentially double down on the idea that random mutations play a big role while trying to clear the air a bit.

First, they basically redid the 2015 analysis, this time including the lifetime risk of 17 types of cancer in people from 69 different countries (so not just people in the US). The data again found a strong correlation between cancer risks and stem cell replication. This is despite the fact that different countries and populations have different genetic and environmental exposures that can also contribute to cancer development.

Next, they pooled genetic sequencing data and epidemiological studies of different types of cancers to see if they could calculate out the role that random mutations played in each of them specifically. It varied quite a bit. For instance, 77 percent of mutations behind pancreatic cancer were calculated to be random, while eight percent were from environmental factors, and up to five percent were due to hereditary factors. For prostate cancer, the researchers calculated that 95 percent of the mutations driving the disease were random.

Overall, they concluded that two-thirds of mutations behind cancers are random. That leaves 29 percent of mutations from environmental and lifestyle factors, and five percent that are inherited.

At first glance, the conclusion seems to echo the incorrect headlines that followed their initial study. But there’s one really important distinction: cancers can be caused by several mutations. Say a cancer develops if a cell acquires three specific mutations: two of those mutations could be random and the third could be induced by some toxic chemical in air pollution. So, avoiding air pollution alone—thus preventing that induced mutation—could prevent the cancer.

In a press conference, Tomasetti and Vogelstein took pains to emphasize that their data was in agreement with prevention efforts and epidemiological data.

In an accompanying commentary, researchers Martin Nowak of Harvard and Bartlomiej Waclaw of the University of Edinburgh argue that the new study offers a useful statistical—but not biological—explanation to cancer development. “An understanding of cancer risk that did not take bad luck into account would be as inappropriate as one that did not take environmental or hereditary factors into account,” they conclude.

Others may see less value in the new report. As Edward Giovannucci, who studies cancer prevention at Harvard, told Nature News in 2015: “By not smoking, your lifetime risk of lung adenocarcinoma drops dramatically… The fact that your risk of pelvic sarcoma is even lower because there’s less stem-cell division—so what?”

Science, 2017. DOI: 10.1126/science.aaf9011 (About DOIs).