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DNA Replication Errors Contribute to 66 Percent of Cancer-Driving Mutations

NEW YORK (GenomeWeb) – Some two thirds of mutations that contribute to the development of cancer may result from DNA replication errors rather than from environmental or hereditary factors, according to researchers from Johns Hopkins University School of Medicine.

Typically, Hopkins' Cristian Tomasetti noted, environmental and inherited factors are considered to be the main drivers of cancer. But he and Hopkins' Bert Vogelstein have found that a third factor — random errors made during cell division — also contribute to disease development. In 2015, they reported in Science that the number of stem cell divisions that took place in certain tissues correlated with the incidence of cancer in those tissues. This suggested to them that errors introduced during replication contributed to cancer risk, events they called "bad luck." 

In a new paper, appearing today in Science, they extended those findings and used a mathematical model to estimate the fraction of mutations attributable to such copying errors.

"Two thirds of the mutations that occur in cancers are due to the mistakes that cells make when they divide," Vogelstein said during a press briefing. He added that "this is in perfect accord with epidemiological estimates that 42 percent of cancers can be prevented and that everyone should adhere to those prevention guidelines."

Typically, Vogelstein noted, every time a normal cell divides, it makes about three errors, and while these errors oftentimes fall in regions where they do not do any harm, they sometimes crop up in cancer-driver genes. In their 2015 paper, Vogelstein and Tomasetti's analysis of this link between the number of stem cell divisions and cancer incidence was limited to the US population. But in this new study, they examined cancer incidence in 69 countries by drawing on 423 cancer registries made available by the International Agency for Research on Cancer.

Using this, they calculated the correlation between the number of stem cell divisions for 17 tissue types for which there was such data and the lifetime incidence of cancer in those tissues. Overall, they calculated a median correlation coefficient of 0.8, similar to what they reported in 2015 for a US population. This suggested to the researchers that the finding was global.

Vogelstein and Tomasetti also set out to determine what fraction of cancer-causing mutations resulted from environmental factors, hereditary factors, and replication errors in 32 cancer types.

Using genome-wide sequencing data from The Cancer Genome Atlas and epidemiological data from the Cancer Research UK database, they developed a mathematical model to try to do just that.

They knew certain information for some of the datasets — for instance, which cancer patients were smokers — and that allowed them to attribute part of their excess of mutations to environmental factors. But they didn't have all that information for all cancer types, so they relied on previously developed mutation rate estimates and cancer incidence rates.

From this, they found that 66 percent of cancer mutations are due to replication errors, 29 percent are due to environmental factors, and 5 percent are due to heredity, Vogelstein said.

However, the researchers also found that these percentages varied by organ.

In pancreatic cancer, they found that 77 percent of mutations were due to random copying errors, 18 percent to environmental factors, and 5 percent to heredity, while for cancers like prostate, bone, and brain, more than 95 percent of the mutations were due to copying errors. For lung adenocarcinoma, the researchers reported that 65 percent of the mutations were due to environmental factors — likely cigarette smoking — and 35 percent to copying errors.

However, Vogelstein and Tomasetti said that this greater-than-expected role of replication errors doesn't mean that a large portion of cancers isn't preventable. Tomasetti noted during the press briefing that three or more mutations are typically needed to drive disease development. For instance, in lung adenocarcinoma, he noted that 90 percent of patients had mutations due to both environmental factors and random replication errors, while the remaining 10 percent had solely random causes. That means, he said, that a large number of cases could theoretically be prevented.

"Even if one mutation is caused by [the environment], if we can prevent that mutation, then that patient would not have had cancer," he added.

This, Vogelstein noted, is in accordance with epidemiological studies that have found that many cancers are preventable.