New research has found that random and unpredictable DNA copying “mistakes” are responsible for nearly two-thirds of the mutations that cause cancer.

This means “environmental” influences, such as nutrition and exercise, play less of a role in many cancer cases than previously thought.

The research from the Johns Hopkins Kimmel Cancer Center was published in the journal Science and used a novel mathematical model to examine data from around the world.

Professor of Biostatistics at the Center, Dr Cristian Tomasetti, says approximately 40 percent of cancers may be prevented by avoiding unhealthy environments and lifestyles.

But he says when cancer strikes those follow all the rules of healthy living — non-smoker, healthy diet, healthy weight, little or no exposure to known carcinogens — it prompts the pained question “Why me?”

“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,” he says.

“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.”

The researchers say that while work needs to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations, many people will still develop cancers due to random DNA copying errors.

Co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center, Dr Bert Vogelstein, says 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,” he says.  

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, the researchers 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 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 Dr 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.”

Dr Tomasetti says 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 Dr Vogelstein. “Nothing you did or didn’t do was responsible for your illness.”

12 April 2017


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