Up to two-thirds of the mutations that drive human cancers may be due to DNA replication errors in normally dividing stem cells, not by inherited or environmentally induced mutations, according to a mathematical modeling study.

The proportion of replication error-driven mutations varied widely among 17 cancers analyzed, but the overall attributable risk of these errors was remarkably consistent among 69 countries included in the study, said Cristian Tomasetti, PhD, a coauthor of the paper and a biostatistician at Johns Hopkins University, Baltimore.

The findings should be a game-changer in the cancer field, Dr. Tomasetti said during a press briefing sponsored by the American Association for the Advancement of Science. Research dogma has long held that most cancers are related to lifestyle and environmental exposure, with a few primarily due to genetic factors.

“We have now determined that there is a third factor, and that it causes most of the mutations that drive cancer,” Dr. Tomasetti said. “We cannot ignore it and pretend it doesn’t exist. This is a complete paradigm shift in how we think of cancer and what causes it.”

The finding that 66% of cancer-driving mutations are based on unavoidable replication errors doesn’t challenge well-established epidemiology, said Dr. Tomasetti and his coauthor, Bert Vogelstein, MD. Rather, it fits perfectly with several key understandings of cancer: that about 40% of cases are preventable, that rapidly dividing tissues are more prone to develop cancers, and that cancer incidence rises exponentially as humans age.

“If we have as our starting point the assumption that 42% of cancers are preventable, we are completely consistent with that,” in finding that about 60% of cancers are unavoidable, Dr. Tomasetti said. “Those two numbers go perfectly together.”

The study also found that replication-error mutations (R) were most likely to drive cancers in tissues with rapid turnover, such as colorectal tissue. This makes intuitive sense, given that basal mutation rates hover at about three errors per cell replication cycle regardless of tissue type.

“The basal mutation rate in all cells is pretty even,” said Dr. Vogelstein, the Clayton Professor of Oncology and Pathology at John Hopkins University, Baltimore. “The difference is the number of stem cells. The more cells, the more divisions, and the more mistakes.”

R-mutations also contribute to age-related cancer incidence. As a person ages, more cell divisions accumulate, thus increasing the risk of a cancer-driving R-error. But these mutations also occur in children, who have rapid cell division in all their tissues. In fact, the colleagues suspect that R-errors are the main drivers of almost all pediatric cancers.

The new study bolsters the duo’s controversial 2015 work.

This illustration depicts the proportion of replication errors, environmental factors, and hereditary factors that drive these cancers.

That paper was the first to suggest that random mutations arising during DNA replication in normal, noncancerous stem cells are an important driver of many cancers. In it, the authors conducted mathematical modeling of the lifetime risk of 32 cancers in a U.S. population and the number of stem cell divisions in each of the associated tissue types. The correlation between these two very different parameters – number of stem cell divisions and lifetime risk – was striking and highly positive. The research showed that 65% of the differences in cancer risk among different tissues could be explained by the total number of stem cell divisions in those tissues.

The theory sparked controversy among scholars and researchers. They challenged it on a number of technical fronts, from stem cell counts and division rates to charges that it didn’t adequately assess the interaction between R-mutations and environmental risks.

Some commentators, perceiving nihilism in the paper, expressed concern that clinicians and patients would get the idea that cancer prevention strategies were useless, since most cancers were simply a case of “bad luck.”

A pervading theme of these counter arguments was one familiar to any researcher: Correlation does not equal causation. The new study was an attempt to expand upon and strengthen the original findings, Dr. Tomasetti said.

“There are well-known environmental risk variations across the world, and there was a question of how our findings might change if we did this analysis in a different country. This paper is also the very first time that someone has ever looked at the proportions of mutations in each cancer type and assigned them to these factors.”

The new study employed a similar mathematical model, but comprised data from 423 cancer registries in 69 countries. The researchers examined the relationship between the lifetime risk of 17 cancers (including breast and prostate, which were not included in the 2015 study) and lifetime stem cell divisions for each tissue. The median correlation coefficient was 0.80; 89% of the countries examined had a correlation of greater than 0.70. This was “remarkably similar” to the correlation determined in the 2015 U.S.-only study.

The team’s next step was to determine what fraction of cancer-driving mutations arose from R-errors, from environmental factors (E), and from hereditary factors (H). They examined these proportions in 32 different cancers in which environmental, lifestyle, and genetic factors have been thoroughly studied. Overall, 29% of the driver mutations were due to environment, 5% to heredity, and 66% to R-errors.

The proportions of these drivers did vary widely between the cancer types, the team noted. For example, lung and esophageal cancers and melanoma were primarily driven by environmental factors (more than 60% each). However, they wrote, “even in lung adenocarcinomas, R contributes a third of the total mutations, with tobacco smoke [including secondhand smoke], diet, radiation, and occupational exposures contributing the remainder. In cancers that are less strongly associated with environmental factors, such as those of the pancreas, brain, bone, or prostate, the majority of the mutations are attributable to R.”

During the press briefing, Dr. Tomasetti and Dr. Vogelstein stressed that most of the inevitable R-errors don’t precipitate cancer – and that even if they do increase risk, that risk may not ever trip the disease process.

“Most of the time these replicative mutations do no harm,” Dr Vogelstein said. “They occur in junk DNA genes, or in areas that are unimportant with respect to cancer. That’s the good luck. Occasionally, they occur in a cancer driver gene, and that is bad luck.”

But even a dose of bad luck isn’t enough to cause cancer. Most cancers require multiple hits to develop – which makes primary prevention strategies more important than ever, Dr. Tomasetti said.

“In the case of lung cancer, for instance, three or more mutations are needed. We showed that these mutations are caused by a combination of environment and R-errors. In theory, then, all of these cancers are preventable because if we can prevent even one of the environmentally caused mutations, then that patient won’t develop cancer.”

However, he said, some cancers do appear to be entirely driven by E-errors and, thus, appear entirely unavoidable. This is an extremely difficult area for clinicians and patients to navigate, said Dr. Vogelstein, a former pediatrician.

“We hope that understanding this will offer some comfort to the literally millions of patients who develop cancer despite having lead a near-perfect life,” in terms of managing risk factors. “Cancer develops in people who haven’t smoked, who avoided the sun and wore sunscreen, who eat perfectly healthy diets and exercise regularly. This is a particularly important concept for parents of children who have cancer, who think ‘I either transmitted a bad gene or unknowingly exposed my child to an environmental agent that caused their cancer.’ They need to understand that these cancers would have occurred no matter what they did.”

Dr. Tomasetti had no disclosures. Dr. Vogelstein is on the scientific advisory boards of Morphotek, Exelixis GP, and Sysmex Inostics, and is a founder of PapGene and Personal Genome Diagnostics.

msullivan@frontlinemedcom.com

On Twitter @Alz_gal

Unavoidable, random DNA replication errors are the most common cancer drivers