'Bad luck' of random mutations plays major role in cancer

Scientists from the Johns Hopkins Kimmel Cancer Center have created a statistical model that measures the proportion of cancer incidence, across many tissue types, caused mainly by random mutations that occur when stem cells divide. By their measure, two-thirds of adult cancer incidence across tissues can be explained primarily by the "bad luck" of random mutations occurring in genes that can drive cancer growth, while the remaining third are due to environmental factors and inherited genes.

"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 each of these three factors contributes to cancer development," says Bert Vogelstein, the Clayton Professor of Oncology at the Johns Hopkins University School of Medicine, co-director of the Ludwig Center at Johns Hopkins, and an investigator at the Howard Hughes Medical Institute.

"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," adds Vogelstein, who cautions that a poor lifestyle can add to the bad luck factor in the development of cancer.

The implications of the researchers' model range from altering public perception about cancer risk factors to the funding of cancer research, they say.

Biomathematician Cristian Tomasetti, an assistant professor of oncology at the Johns Hopkins schools of Medicine and Public Health, says, "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. We should focus more resources on finding ways to detect such cancers at early, curable stages."

In a report on the statistical findings, published recently in Science, Tomasetti and Vogelstein say they came to their conclusions by searching the scientific literature for information on the cumulative total number of divisions of stem cells among 31 tissue types during an average individual's lifetime. Stem cells "self-renew," thus repopulating cells that die off in a specific organ.

It was well-known, Vogelstein notes, that cancer arises when tissue-specific stem cells make random mistakes when one chemical letter in DNA is incorrectly swapped for another during the replication process in cell division. The more these mutations accumulate, the higher the risk that cells will grow unchecked, a hallmark of cancer. The actual contribution of these random mistakes to cancer incidence, in comparison to the contribution of hereditary or environmental factors, was not previously known, says Vogelstein.

The scientists note that some cancers, such as breast and prostate cancers, were not included in the report because they were unable to find reliable stem cell division rates in the scientific literature. They hope that other scientists will help refine their statistical model by finding more-precise stem cell division rates for other types of cancers.

The research was funded by the Virginia and D.K. Ludwig Fund for Cancer Research, Lustgarten Foundation for Pancreatic Cancer Research, Sol Goldman Pancreatic Cancer Research Center, and National Cancer Institute.

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