Most cancer mutations are due to random DNA copying 'mistakes'

"It is well-known that we must avoid environmental factors such as smoking to decrease our risk of getting cancer. But it is not as well-known that each time a normal cell divides and copies its DNA to produce two new cells, it makes multiple mistakes," says Cristian Tomasetti, Ph.D., assistant professor of biostatistics at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health. "These copying mistakes are a potent source of cancer mutations that historically have been scientifically undervalued, and this new work provides the first estimate of the fraction of mutations caused by these mistakes."

"We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations. However, many people will still develop cancers due to these random DNA copying errors, and better methods to detect all cancers earlier, while they are still curable, are urgently needed," says Bert Vogelstein, M.D., co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center.

Tomasetti and Vogelstein conducted the new study described in a report published March 24 in the journal Science.

The researchers say their conclusions are in accord with epidemiologic studies showing that approximately 40 percent of cancers can be prevented by avoiding unhealthy environments and lifestyles. But among the factors driving the new study, say the researchers, is that cancer often strikes people who follow all the rules of healthy living -- nonsmoker, healthy diet, healthy weight, little or no exposure to known carcinogens -- and have no family history of the disease, prompting the pained question "Why me?"

Tomasetti and Vogelstein believe the answer to this question rests in random DNA copying errors. Current and future efforts to reduce known environmental risk factors, they say, will have major impacts on cancer incidence in the U.S. and abroad. But they say the new study confirms that too little scientific attention is given to early detection strategies that would address the large number of cancers caused by random DNA copying errors.

"These cancers will occur no matter how perfect the environment," says Vogelstein.

In a previous study authored by Tomasetti and Vogelstein in the Jan. 2, 2015, issue of Science, the pair reported that DNA copying errors could explain why certain cancers in the U.S., such as those of the colon, occur more commonly than other cancers, such as brain cancer.

In the new study, the researchers addressed a different question: What fraction of mutations in cancer are due to these DNA copying errors?

To answer this question, the scientists took a close look at the mutations that drive abnormal cell growth among 32 cancer types (Supplemental Materials, Table S6). They developed a new mathematical model using DNA sequencing data from The Cancer Genome Atlas and epidemiologic data from the Cancer Research UK database.

According to the researchers, it generally takes two or more critical gene mutations for cancer to occur. In a person, these mutations can be due to random DNA copying errors, the environment or inherited genes. Knowing this, Tomasetti and Vogelstein used their mathematical model to show, for example, that when critical mutations in pancreatic cancers are added together, 77 percent of them are due to random DNA copying errors, 18 percent to environmental factors, such as smoking, and the remaining 5 percent to heredity.

In other cancer types, such as those of the prostate, brain or bone, more than 95 percent of the mutations are due to random copying errors.

Lung cancer, they note, presents a different picture: 65 percent of all the mutations are due to environmental factors, mostly smoking, and 35 percent are due to DNA copying errors. Inherited factors are not known to play a role in lung cancers.

Looking across all 32 cancer types studied, the researchers estimate that 66 percent of cancer mutations result from copying errors, 29 percent can be attributed to lifestyle or environmental factors, and the remaining 5 percent are inherited.

The scientists say their approach is akin to attempts to sort out why "typos" occur when typing a 20-volume book: being tired while typing, which represents environmental exposures; a stuck or missing key in the keyboard, which represent inherited factors; and other typographical errors that randomly occur, which represent DNA copying errors. "You can reduce your chance of typographical errors by making sure you're not drowsy while typing and that your keyboard isn't missing some keys," says Vogelstein. "But typos will still occur because no one can type perfectly. Similarly, mutations will occur, no matter what your environment is, but you can take steps to minimize those mutations by limiting your exposure to hazardous substances and unhealthy lifestyles."

Tomasetti and Vogelstein's 2015 study created vigorous debate from scientists who argued that their previously published analysis did not include breast or prostate cancers, and it reflected only cancer incidence in the United States.

However, Tomasetti and Vogelstein now report a similar pattern worldwide, supporting their conclusions. They reasoned that the more cells divide, the higher the potential for so-called copying mistakes in the DNA of cells in an organ. They compared total numbers of stem cell divisions with cancer incidence data collected by the International Agency for Research on Cancer on 423 registries of cancer patients from 68 countries other than the U.S., representing 4.8 billion people, or more than half of the world's population. This time, the researchers were also able to include data from breast and prostate cancers. They found a strong correlation between cancer incidence and normal cell divisions among 17 cancer types, regardless of the countries' environment or stage of economic development.

Tomasetti says these random DNA copying errors will only get more important as societies face aging populations, prolonging the opportunity for our cells to make more and more DNA copying errors. And because these errors contribute to a large fraction of cancer, Vogelstein says that people with cancer who have avoided known risk factors should be comforted by their findings. "It's not your fault," says Vogelstein. "Nothing you did or didn't do was responsible for your illness."

In addition to Tomasetti and Vogelstein, Lu Li, a doctoral student in Tomasetti's laboratory in the Department of Biostatistics at the Johns Hopkins Bloomberg School of Public Health, also contributed to the research. Funding for the research was provided by the John Templeton Foundation, the Lustgarten Foundation for Pancreatic Cancer Research, the Virginia and D.K. Ludwig Fund for Cancer Research, the Sol Goldman Center for Pancreatic Cancer Research, and the National Institutes of Health's National Cancer Institute (CA006973, CA43460, and CA62924).

Vogelstein is a member of the scientific advisory boards of Morphotek, Exelixis GP, and Syxmex Inostics, and is a founder of PapGene and Personal Genome Diagnostics. Morphotek, Syxmex Inostics, PapGene, and Personal Genome Diagnostics, as well as other companies, have licensed technologies from The Johns Hopkins University on which Vogelstein is an inventor. These licenses and relationships are associated with equity or royalty payments to Vogelstein. The terms of these arrangements are being managed by The Johns Hopkins University in accordance with its conflict of interest policies.