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Random Errors in DNA Replication Play Major Role in Cancer

Cristian Tomasetti and Bert Vogelstein of the Johns Hopkins Kimmel Cancer Center speak at a 22 March press briefing at AAAS. | Neil Orman/ AAAS

Nearly two-thirds of mutations in human cancers are attributable to random errors that occur naturally in healthy, dividing cells during DNA replication, researchers report in the 24 March issue of Science.

Though mutations that cause human cancer have traditionally been thought to originate from heredity or environmental sources, these results — grounded in a novel mathematical model based on data from around the world — support a role for so-called "R" or random mutations in driving the disease.

"This is the very first time researchers have looked at the proportions of mutations within different cancer types and assigned them to these three factors," said lead author Cristian Tomasetti, assistant professor of biostatistics at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health, referring to heredity, environmental and random factors.

"Up until now, there has been very little attention given to R mutations," said senior author Bert Vogelstein, co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center. "We hope that one implication of our research is to inspire many scientists to devote their efforts to strategies that could limit the damage these particular mutations." He added, "Better methods to detect all cancers earlier, while they are still curable, are urgently needed."

Among the factors driving their new study, Vogelstein said, was that cancer often strikes people who follow all the rules of healthy living — not smoking, eating a healthy diet and exercising, for example, and with no family history of the disease — prompting the pained question, "Why me?"

"We hope that this research offers comfort to millions of patients like this," said Vogelstein. "This is particularly important in cases of children and the parents of children who have cancer, helping them understand the root causes of this disease."

Vogelstein and Tomasetti presented their findings to reporters during a 22 March press briefing at the American Association for the Advancement of Science's headquarters.

While it has been well-established that people should avoid behaviors like smoking to decrease cancer risk, it is less well-known that each time a normal cell divides and copies its DNA to produce two new cells, it makes multiple mistakes.

"These copying mistakes are a potent source of cancer mutations," said Tomasetti, "and historically, these mutations have been undervalued."

In 2015, Tomasetti and Vogelstein published a widely covered Science paper that found that R mutations explain the dramatic variation in cancer incidence among human tissues better than hereditary or environmental factors — helping to illuminate why tissues in the lung or colon give rise to cancer far more frequently than tissues in bone or brain, for example.

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Bert Vogelstein discussed cancer prevention strategies at the AAAS briefing.| Neil Orman/ AAAS

The study created vigorous debate from scientists who argued that the 2015 analysis did not include breast or prostate cancers, which are more common, and reflected only cancer incidence in the United States.

In their new study, Vogelstein and Tomasetti, working with global data, sought to answer a different question: What fraction of cancer mutations is due to R mutations?

To answer that question, they analyzed genome sequencing data from The Cancer Genome Atlas and epidemiologic data from the Cancer Research UK database, developing a mathematical model that allowed them to determine the proportion of cancer mutations that resulted from R, hereditary or environmental mutations, respectively.

They ultimately found that about two-thirds of mutations in the 32 cancers they analyzed were attributable to random errors in DNA replication. This correlation even held up in cancers such as breast and prostate cancer, which had not been studied in the 2015 paper.

In a second analysis including data from 69 countries spanning six continents, Tomasetti and Vogelstein found that the high correlation between cancer incidence and R mutations they had previously reported in 2015 persisted — even in countries with widely different environments. This confirmed that peculiarities of the U.S. population or environment could not explain the previously identified correlation between cancer incidence and R, they said.

Critically, the findings underscore the need for more research efforts focused on secondary prevention, which would include early detection and early intervention. For cancers in which all mutations are random, secondary prevention — done not to prevent cancer, but to reduce cancer death — may be the only option, the researchers said.

For cancers in which only a small percentage of mutations are due to random DNA replication errors, by contrast, primary prevention efforts — those aimed at minimizing harmful environmental exposures — will continue to be the most effective way to reduce cancer deaths, the researchers said.

"We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations," said Vogelstein.

He emphasized that the results of their study are fully consistent with evidence on the fraction of cancers in developed countries that are potentially preventable, through improvements in environment and lifestyle. Cancer Research UK, for example, estimates that 42% of cancer cases are preventable, while the U.S. Centers for Disease Control and Prevention estimates that 21% of annual cancer deaths can be prevented.

Vogelstein and Tomasetti are optimistic that their results will encourage the scientific community to improve methods to detect all cancers earlier. A better understanding of the mutations that cause human cancer, they said, will help to define the best strategies for reducing cancer deaths.

[Credit for associated image: Chris Bickel/ Science]