They’re ba-ack. The scientists who caused a stir 2 years ago—by reporting that DNA copying errors could explain most of the differences in cancer risk among different tissues—have expanded their findings. They now address a more general question: What fraction of mutations in cancer are due to DNA copying errors, as opposed to genetic inheritance or lifestyle factors.

The researchers, Cristian Tomasetti, Ph.D., and Bert Vogelstein, M.D., both of Johns Hopkins Kimmel Cancer Center, examined 32 cancer types, compared cancer incidence and stem cell division rates, and estimated that 66% of cancer mutations result from copying errors. Lifestyle or environmental factors and inherited factors account for 29% and 5% of cancer mutations, respectively.

Details of the scientists’ results appeared March 24 in the journal Science, in an article entitled “Stem Cell Divisions, Somatic Mutations, Cancer Etiology, and Cancer Prevention.” This article, unlike the one that appeared 2 years ago, extends the researchers’ analysis to breast cancer and prostate cancer. In addition, the new study reflects cancer incidence data that is international in scope, and is not limited to cancer incidence in the United States.

“We studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries throughout the world,” the article’s authors wrote. “The data revealed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of their environment.”

Cancers, the authors noted, are caused by mutations that may be inherited, induced by environmental factors, or result from DNA replication errors (R).

“The major role of R mutations in cancer etiology was supported by an independent approach, based solely on cancer genome sequencing and epidemiological data, which suggested that R mutations are responsible for two-thirds of the mutations in human cancers,” they continued. “All of these results are consistent with epidemiological estimates of the fraction of cancers that can be prevented by changes in the environment.”

The new findings are bound to be provocative, if only because they force us to confront basic attitudes about the relationship between chance, misfortune, and the degree to which humans can exert control over their own fates.

“It is well-known that we must avoid environmental factors such as smoking to decrease our risk of getting cancer,” said Dr. Tomasetti. “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. 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,” added Dr. Vogelstein. “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.”

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?”

Drs. 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 United States 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,” noted Dr. Vogelstein.

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

The new study finds that 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, Drs. 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.

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,” explained 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.”








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