Statistical model shows random mutations play a dominant role in cancer development

Scientists 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 as bad luck, due to 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 of these three factors contribute to cancer development," said Bert Vogelstein, MD, the Clayton Professor of Oncology at the Johns Hopkins University School of Medicine, co-director of the Ludwig Center at Johns Hopkins Kimmel Cancer Center, and an investigator at the Howard Hughes Medical Institute in Baltimore, Maryland.

"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," added Vogelstein, who cautioned that poor lifestyles can add to the bad luck factor in the development of cancer.

The implications of this model range from altering public perception about cancer risk factors to the funding of cancer research, report Vogelstein's team.

"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," said biomathematician Cristian Tomasetti, PhD, an assistant professor of oncology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health. "We should focus more resources on finding ways to detect such cancers at early, curable stages."

In a report on the statistical findings, published in Science (2015; doi:10.1126/science.1260825), 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 person's lifetime. Stem cells self-renew, thus repopulating cells that die off in a specific organ.

It was well-known, Vogelstein noted, that cancer arises when tissue-specific stem cells make random mistakes, or mutations, 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.

"We found that the types of cancer that had higher risk than predicted by the number of stem cell divisions were precisely the ones you'd expect, including lung cancer, which is linked to smoking; skin cancer, linked to sun exposure; and forms of cancers associated with hereditary syndromes," said Vogelstein.

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