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Random mutations responsible for most cancers

Scientists from the Johns Hopkins Kimmel Cancer Centre have created a statistical model that measures the proportion of cancer risk, across many tissue types, caused mainly by random mutations that occur when stem cells divide. By their measure, two-thirds of the variation in adult cancer risk across tissues can be explained primarily by "bad luck," when these random mutations occur 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," says Dr Bert Vogelstein, the Clayton professor of oncology at the Johns Hopkins University School of Medicine.

"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 poor lifestyles can add to the bad luck factor in the development of cancer.

The implications of their model range from altering public perception about cancer risk factors to the funding of cancer research, they say. "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," says bio-mathematician Dr Cristian Tomasetti, 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," he adds.

In a report on the statistical findings, 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, 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, says Vogelstein.

To sort out the role of such random mutations in cancer risk, the Johns Hopkins scientists charted the number of stem cell divisions in 31 tissues and compared these rates with the lifetime risks of cancer in the same tissues among Americans. From this so-called data scatterplot, Tomasetti and Vogelstein determined the correlation between the total number of stem cell divisions and cancer risk to be 0.804. Mathematically, the closer this value is to one, the more stem cell divisions and cancer risk are correlated.

"Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue," says Vogelstein. One example, he says, is in colon tissue, which undergoes four times more stem cell divisions than small intestine tissue in humans. Likewise, colon cancer is much more prevalent than small intestinal cancer.

"You could argue that the colon is exposed to more environmental factors than the small intestine, which increases the potential rate of acquired mutations," says Tomasetti. However, the scientists saw the opposite finding in mouse colons, which had a lower number of stem cell divisions than in their small intestines, and, in mice, cancer incidence is lower in the colon than in the small intestine. They say this supports the key role of the total number of stem cell divisions in the development of cancer.

Using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65%.

Finally, the research duo classified the types of cancers they studied into two groups. They statistically calculated which cancer types had an incidence predicted by the number of stem cell divisions and which had higher incidence. They found that 22 cancer types could be largely explained by the "bad luck" factor of random DNA mutations during cell division. The other nine cancer types had incidences higher than predicted by "bad luck" and were presumably due to a combination of bad luck plus environmental or inherited factors.

“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,” says Vogelstein.

"This study shows that you can add to your risk of getting cancers by smoking or other poor lifestyle factors. However, many forms of cancer are due largely to the bad luck of acquiring a mutation in a cancer driver gene regardless of lifestyle and heredity factors. The best way to eradicate these cancers will be through early detection, when they are still curable by surgery," adds Vogelstein.

The scientists note that some cancers, such as breast and prostate cancer, were not included in the report because of their inability 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.

Healthier lifestyles could have prevented almost 600,000 cases of cancer in the UK over the last five years. The Independent reports that a new study from Cancer Research UK indicates four out of 10 cases could have been avoided if people had made lifestyle changes.

Giving up smoking would have had the biggest impact on reducing cancer – leading to more than 314,000 fewer cases since 2009.

However, a further 145,000 cases could have been prevented if people had adopted a balanced diet low in red and processed meat and salt and high in vegetables.

In addition, maintaining a healthy weight could have prevented a further 88,000 cases, while thousands more were linked to excess alcohol, failing to protect skin from the sun and lack of exercise.

"There's now little doubt that certain lifestyle choices can have a big impact on cancer risk with research around the world all pointing to the same key risk factors," said Professor Max Parkin, from Queen Mary, University of London, who provided the statistical evidence for the report.

"Leading a healthy lifestyle can’t guarantee someone won’t get cancer but we can stack the odds in our favour by taking positive steps now that will help decrease our cancer risk in future," Professor Linda Bauld, Cancer Research UK’s expert on cancer prevention, added: "There are more than 200 types of cancer, each caused by a complex set of factors involving both our genes and our lifestyles. There are proven ways to minimise our risk of cancer, like giving up smoking, being more active, drinking less alcohol and maintaining a healthy weight. We must make sure the public and the policy-makers know the evidence behind the benefits of these lifestyle changes is solid."

[link url="http://www.hopkinsmedicine.org/news/media/releases/bad_luck_of_random_mutations_plays_predominant_role_in_cancer_study_shows"]Johns Hopkins School of Medicine release[/link]
[link url="http://www.sciencemag.org/content/347/6217/78.abstract"]Science abstract[/link]
[link url="http://www.independent.co.uk/life-style/health-and-families/health-news/healthy-living-could-have-prevented-half-a-million-cancer-cases-over-last-five-years-9944945.html"]Full report in The Independent[/link]
[link url="http://www.nature.com/bjc/journal/v112/n1/full/bjc2014569a.html#close"]British Journal of Cancer abstract[/link]

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