For each of 18 representative cancer types, the schematic depicts the proportion of mutations that are inherited, due to environmental factors, or due to errors in DNA replication (i.e., not attributable to either heredity or environment). The sum of these three proportions is 100%. Photo: Johns Hopkins University

While environmental and inherited factors have well-known roles in cancer development, a new study provides evidence that a third, and until this point scientifically undervalued factor, is at the root of nearly two-thirds of cancer-causing mutations: random and unpredictable errors that occur in normal DNA replication.

Cells are constantly regenerating, and every time a healthy cell divides, there are about three random mistakes or mutations in the copied DNA. Most of the time these copying errors are harmless. However, occasionally they occur in a cancer driver gene, which is just “bad luck,” study author Bert Vogelstein, M.D., co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center, said at a press conference about the research.

Using a new mathematical model based on DNA sequencing and epidemiologic data from countries around the world, the paper, published March 24 in Science, is the first to calculate how many of the mutations found in cancers are due to environmental factors, heredity, or these random DNA copying errors.

Overall, when looking at 32 cancer types, the researchers, including Cristian Tomasetti, assistant professor of biostatistics, found that about 66 percent of the total mutations are due to random DNA copying errors, 29 percent are due to environmental factors, and the remaining 5 percent are caused by inherited factors.

At the press conference, Tomasetti and Vogelstein emphasized that these figures are consistent with epidemiologic studies, such as one from Cancer Research UK, which estimates about 42 percent of cancers are preventable through avoiding unhealthy environments and lifestyles.

A healthy lifestyle

Although these random copying errors are unavoidable, it usually takes two or more critical gene mutations for cancer to develop, according to the researchers.

Looking specifically at mutations in pancreatic cancers, the study showed 77 percent are due to random errors in DNA replication, 18 percent owing to environment and 5 percent to inherited factors.

For other cancer types, such as brain and bone, random copying errors have even more of an influence. For example, 95 percent of the driver gene mutations in prostate cancers can be attributed to factors other than environmental or inherited, presumably random copying errors, the authors write.

Lung cancer, however, is different. The researchers concluded that 65 percent of all the mutations in lung cancer are due to environmental factors, mostly smoking, while 35 percent are caused by DNA copying errors.

At the press conference, Vogelstein said he hoped this research would offer comfort to millions of patients who have developed cancers despite living healthy lifestyles, helping them feel less guilty about contracting the disease since mutations are unavoidable. It’s particularly important for parents of a child with cancer, Vogelstein, a former pediatrician, said, as they often assume it’s an environmental or hereditary cause and blame themselves.

“These cancers will occur no matter how perfect the environment,” Vogelstein said in a prepared statement.

The authors stressed that people should still abide by healthy guidelines and avoid environmental factors, such as smoking, to decrease the risk of getting cancer. Still, more attention must be paid to early detection methods, which for now are the only tools against mutations driven by random DNA copying errors.    

In a 2015 Science paper, authored by Tomasetti and Vogelstein, the pair said random DNA copying errors could be the reason why some cancers, such as colon, are more prevalent in the U.S. than others, like brain cancer, because of the amount of cell division happening in the tissue. They reasoned the more cell division happening, the greater the potential for random DNA copying mistakes.

The paper caused much debate in the scientific community, and some criticized that the analysis was limited to the U.S. and did not take into account breast or prostate cancers.

In the new study, the authors compared the total numbers of stem cell divisions with cancer incidence in 69 countries around the world, with varying environments, representing two-thirds, or 4.8 billion people.  Cancer incidences were determined from analysis of 432 cancer registries collected by the International Agency for Research on Cancer.

The researchers found strong, statistically significant correlations between the lifetime risk of cancer in a given tissue among 17 cancer types and the number of stem cell divisions in that tissue’s lifetime. The correlations between normal stem cell divisions and cancer incidences was universally high across all countries, regardless of economic development or environment. This time around, the analysis did include data from breast and prostate cancers.

Defeating the enemy

The likelihood of mutations increases with age, simply because the longer a person lives, the more chances cells have to replicate and subsequently make copying errors. 

While primary prevention — stopping cancer from occurring in the first place — is the best method for avoiding cancers that are driven mostly by environmental factors, a completely new strategy is needed to defeat these “internal enemies,” Vogelstein said.

Up until now, very little attention has been paid to this threat but the researchers are now confident that what Vogelstein referred to as enemies are already inside humans.

“We hope the work will inspire many scientists to recognize this fact and devote their efforts to strategies to limit the damage these internal enemies do,” Vogelstein said at the press conference. “We believe the first step is simply recognizing that these enemies exist and they’re already here.”

Still, some scientists aren’t convinced random DNA copying mistakes have as much influence as the recent paper suggests.

Dr. Yusuf Hannun, Stony Brook University’s cancer center director told The Associated Press that the new study exaggerates the effect of unavoidable DNA mistakes. The news outlet reported that Hannun’s own research in 2015 found the errors account for 10 to 30 percent of cancer cases.