Random DNA copying errors cause two-thirds of cancer

March 24, 2017

Random, unpredictable mistakes that occur during cell copying cause almost two-thirds of the mutations that cause cancer, according to a new study by scientists at the Johns Hopkins Kimmel Cancer Center in the US.

The data from the research is grounded on a novel mathematical model based on DNA sequencing and epidemiologic data from around the world.

It is common knowledge to avoid certain environmental factors such as smoking to decrease the risk of developing cancer. However, the fact that a normal cell makes multiple mistakes each time it divides and copies its DNA to produce new cells is not as well-known, said 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,” Tomasetti added.

“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.

The researchers say their conclusions are in accord with epidemiologic studies showing that approximately 40% 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 US 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, the pair reported that DNA copying errors could explain why certain cancers in the US, 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. 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% of them are due to random DNA copying errors, 18% to environmental factors, such as smoking, and the remaining 5% to heredity.

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

Lung cancer, they note, presents a different picture: 65% of all the mutations are due to environmental factors, mostly smoking, and 35% 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% of cancer mutations result from copying errors, 29% can be attributed to lifestyle or environmental factors, and the remaining 5% 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 US, 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.”

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