Random mistakes made during DNA replication are responsible for about two-thirds of the mutations that cause human cancers, according to a study reported in Science.¹ Recognizing the role of these replication errors “does not diminish the importance of primary prevention but emphasizes that not all cancers can be prevented by avoiding environmental risk factors,” the study concluded.

“Everybody gets these mutations all the time, and usually it is not a problem,” because the mistakes that a cell makes when it divides “usually occur in regions of the genome that are unimportant for cancer,” Bert Vogelstein, MD, one of the study’s corresponding author, explained in an interview with The ASCO Post. “But very rarely, there will be a mistake in the cancer driver gene, and that will initiate the process of tumor genesis or make it progress if there is already another mutation,” Dr. Vogelstein continued, and that process “is unavoidable.” Dr. Vogelstein is Director of the Ludwig Center for Cancer Genetics and Therapeutics, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore. He is also an investigator at the Howard Hughes Medical Institute and a Distinguished Scholar of the Lustgarten Foundation, Baltimore.

An Important Distinction

It is important “to make this distinction that some cancers in some people are unavoidable” and are not the result of environmental factors or heredity or actions patients did or did not take, Dr. Vogelstein stressed. “Although we certainly don’t want people to have a nihilistic attitude that there is nothing that they can do. We don’t want people to feel guilty,” if they do develop cancer, he continued. “And we definitely want to encourage them to do the right thing” in terms of cancer prevention.

The study builds on analyses confined to the U.S. population and reported in 2015; they found that most of the variation in cancer risk “is due to ‘bad luck,’ that is random mutations rising during DNA replication in normal, noncancerous cells.”² Asked if “bad luck” was an apt term, Dr. Vogelstein said, “I think it is. We could say, ‘the stochastic effect of DNA replication,’ but that doesn’t really roll off the tongue. So, it is bad luck.”

Strong Correlation

“In this study, we have evaluated cancer incidence in 69 countries, representing a variety of environments distributed throughout the world and representing 4.8 billion people (two-thirds of the world’s population),” reported lead author Cristian Tomasetti, PhD, of Johns Hopkins University School of Medicine and Dr. Vogelstein. 

“The data revealed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of their environment. The major role of replication error mutations in cancer etiology was supported by an independent approach, based solely on cancer genome sequencing and epidemiologic data, which suggested that replication error mutations are responsible for two-thirds of the mutations in human cancers,” the authors reported.

Multiple Mutations

“Our results are fully consistent with epidemiologic evidence on the fraction of cancers in developed countries that are potentially preventable through improvements in environment and lifestyle,” the researchers reported. This included estimates from Cancer Research UK that 42% of cancer cases are preventable “if people avoided known carcinogens like cigarette smoke and ultraviolet light,” Dr. Vogelstein added, “and also took seriously the behavioral guidelines issued, such as watching one’s weight. Obesity certainly is a major factor for cancer.”

The study report points out that “the proportion of mutations caused by environmental factors is always less than the proportion of cancers preventable by an avoidance of these factors.” According to Dr. Vogelstein, that is an important point. “If it takes three mutations to get a cancer and two of them are caused by these random factors, and one of them in an individual patient is caused by an environmental factor, that cancer is still preventable. So even though the environmental factor is one-third of the total mutations, cancer is still preventable in that case. It is only not preventable if all three mutations are due to bad luck.”

Role of Random Mutations Varies

“Epidemiologic studies have estimated that nearly 90% of adenocarcinomas of the lung are preventable and that tobacco smoke is by far the major component” among the environmental factors,” the researchers wrote. “Secondhand smoking, occupational exposures, ionizing radiation, air pollution, and diet play important but smaller roles. Moreover, no hereditary factors have been implicated in lung adenocarcinomas.” Using an analytic approach “based on the integration of genome-wide sequencing and epidemiologic data,” the researchers determined that 35% of the driver mutations in lung cancer can be attributed to random mutations.

Every time a cell divides, it gets mutations. These mutations are no different from those caused by environmental agents, and perhaps there is a way to inhibit their occurrence with some sort of chemopreventive agent.

— Bert Vogelstein, MD

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“This same analytic approach can be applied to cancer types for which epidemiologic studies have indicated a less pronounced role of environmental factors,” the researchers reported. Applying it to pancreatic ductal adenocarcinomas, thought to be preventable in about 37% of cases, they “calculated that 18% of the driver gene mutations were due to environmental factors, at most 5% were due to hereditary factors, and the remaining 77% (95% confidence interval: 67%–84%) were due to nonenvironmental and nonhereditary factors, presumably replication errors.”

There are also “certain types of cancer, for sure, in which the environment seems to play a little role—brain tumors, bone cancers, prostate cancers, the great majority of pediatric tumors,” Dr. Vogelstein noted. “But in most other cancer types, it is a mixture, and some patients will acquire the mutations required for cancer because they have exposed themselves to environmental factors or not paid careful attention to the guidelines. Others who have even very carefully adhered to the guidelines will still develop cancer. This is complex, and the reason for the complexity in part is because cancers are multifactorial. Each cancer is caused by multiple mutations.”

Smaller Role for Heredity

Although heredity has a smaller role in cancer causation than random mutations or environmental factors, “perhaps 1/20th of the total cancers,” Dr. Vogelstein said, “it is very important to recognize” hereditary factors such as BRCA and mismatch repair–deficient gene in Lynch syndrome. “Now that the etiology of Lynch syndrome is understood, there is even a drug specifically for Lynch syndrome,” Dr. Vogelstein added, citing a study published in The New England Journal of Medicine on the use of an anti–programmed cell death protein 1 (PD-1) agent to treat people with Lynch syndrome.³

“Once you understand the etiology, it is not just a familial cancer syndrome. It is caused by a specific genetic alteration, which has consequences you can understand genetically and biochemically,” Dr. Vogelstein commented. “And once you understand that, you can begin to rationally try to do something about it.”

Avoidable in the Future?

“Replication error mutations appear unavoidable now, but it is conceivable they will become avoidable in the future,” the authors noted. “There are at least four sources of replication error mutations in normal cells: quantum effects on base pairing, mistakes made by polymerases, hydrolytic deamination of bases, and damage by endogenously produced reactive oxygen species or other metabolites. The last of these sources could theoretically be reduced by the administration of antioxidant drugs. The effects of all four could, in principle, be reduced by introducing more efficient repair genes into the nuclei of somatic cells or through other creative means.”

None of these approaches are near fruition, however, in part “because no one has paid much attention to these random mutations. It has just not been on the radar,” Dr. Vogelstein commented. The publication of the study in Science and news reports in the national media, including The Washington Post, Los Angeles Times, CNN, and NPR should serve to increase recognition of the role of random mutations in the development of cancer. “Once it is recognized, we hope people will start working on it, because some of the mutations may indeed be avoidable through the future development of specific chemopreventative agents,” Dr. Vogelstein added.

“What we try to emphasize is this article is the etiology,” Dr. Vogelstein said. “It is not just risk in the classic epidemiology sense. We are trying to connect what is called risk to the basic genetics that underlie cancer. Every time a cell divides, it gets mutations. These mutations are no different from those caused by environmental agents, such as cigarette smoke or sunlight, and perhaps there is a way to inhibit their occurrence with some sort of chemopreventive agent. But if no one does research on it, we will never find those agents.” ■

Disclosure: Dr. Vogelstein reported no conflicts of interest, as detailed in the paper in Science.

References

1. Tomasetti C, Li L, Vogelstein B: Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention. Science 355:1330-1334, 2017.

2. Tomasetti C, Vogelstein B: Cancer etiology: Variation in cancer risk among tissues can be explained by the number of stem cell divisions. Science 347:78-81, 2015.

3. Le DT, Uram JN, Wang H, et al: PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med 372:2509-2520, 2015.