‘Bad luck’ mutations increase cancer risk more than behavior, study says

For the first time, researchers have estimated what percentage of cancer mutations are due to environmental and lifestyle factors, hereditary factors and random chance. Overall, 66% of the genetic mutations that develop into cancer are caused by simple random errors occurring when cells replace themselves, according to a new study published in the journal Science.

Environmental factors contribute 29% of mutations, while the remaining 5% are inherited, say Cristian Tomasetti and Dr. Bert Vogelstein, both of Johns Hopkins University.

In a previous paper, Tomasetti and Vogelstein asserted that your risk of developing cancer is largely based on random DNA errors that occur when self-renewing cells divide. In their new paper, they offer more detail describing how dumb luck plays a more significant role than either environmental, lifestyle or hereditary factors in causing this disease.

“Every time a perfectly normal cell divides, as you all know, it makes several mistakes – mutations,” explained Vogelstein in a briefing. “Now most of the time, these mutations don’t do any harm. They occur in junk DNA, genes unrelated to cancer, unimportant places with respect to cancer. That’s the usual situation and that’s good luck.”

Occasionally, one of these random miscopies will occur in a cancer driving gene.

“That’s bad luck,” said Vogelstein.

Though this fact may be demoralizing to some people, researchers noted it might bring comfort to people with cancers they worked to prevent or the parents of children with cancer.

Your lifestyle still matters

In a previous research paper published in 2015, Tomasetti and Vogelstein used a mathematical model to first present this idea that cancer risk is strongly correlated with the total number of divisions undergone by normal cells. For 31 cancers, the researchers first estimated the number of stem cells in tissues where disease arose and then they estimated the rate at which these cells divide. Comparing these to incidence of these cancers in the United States, the two researchers found a strong correlation between cell division and lifetime risk of each given cancer.

For their new study, Tomasetti and Vogelstein worked with Lu Li, a doctoral student at Johns Hopkins Bloomberg School of Public Health, to analyze genome sequencing and epidemiologic data from 32 cancer types, including breast and prostate cancers. This time, the research team concluded that nearly two-thirds of mutations in these cancers are attributable to random errors that occur naturally in healthy, dividing cells during DNA replication.

Drilling deeper, they searched 423 international cancer databases to examine data from 69 countries spanning 6 continents, representing 4.8 billion people or two-thirds of the world’s population. Then, as they’d done in their previous study, they estimated stem cell divisions in different human tissues and compared this to lifetime incidence of 17 cancer types.

Once again, their new mathematical model showed a high correlation between cancer incidence and the total number of divisions of normal cells. This time, though, their finding that 66% of all genetic mutations leading to cancer are caused by random errors crossed borders and so ranged across many different potential environmental factors that might lead to cancer.

While this randomness is upsetting, even mutations caused by environmental or lifestyle factors are haphazard, explained Tomasetti.

Take smoking: Cigarette smoking undoubtedly leads to more genetic mutations than might normally happen, yet where the DNA defects occur on a smoker’s genome is completely accidental. In other words, mutations caused by smoking, just like random mutations, can affect either cancer driving genes or stretches of DNA that are irrelevant to cancer.

Lifestyle factors still matter for cancer prevention.

Just one mutation is not sufficient to cause cancer – typically three or more mutations must occur, Tomasetti noted. If, say, your cells miscopy DNA and so cause two random mutations, a third mutation is still needed. Obesity, smoking, lack of exercise and poor eating habits might supply that necessary third gene defect that tips your body into a disease state.

The new study, then, does not let us off the hook: We play a role in protecting our good health.

Paradigm shift

Since the 1970s, the accepted wisdom underlying cancer research was that genomic alterations caused cancer and most of these alterations are mutations, explained Tomasetti. As envisioned by scientists, DNA defects cause the haywire growth of cells which disturb the natural processes of your body.

Naturally, that leaves one fundamental question: What causes these mutations?

Widespread belief suggests the majority of cancers are caused by behavioral and environmental factors, with inherited genetic mutations causing the remainder of cases.

“This is the current paradigm and we feel that our new research breaks this paradigm,” said Tomasetti. “We discovered there’s a third factor that actually causes most of the mutations – random errors made during normal cell division.

So why was this never appreciated before? “It was never measured before and when you measure something you can have a sense of how important that is,” said Tomasetti.

In an editorial published alongside the new study, Martin A. Nowak, a professor of mathematics and biology at Harvard University, and Bartlomiej Waclaw, a researcher at University of Edinburgh, wrote that a large portion of the variation in cancer risk among tissues can be explained, in the statistical sense, by the number of stem cell divisions.

“An understanding of cancer risk that did not take bad luck into account would be as inappropriate as one that did not take environmental or hereditary factors into account,” Nowak and Waclaw wrote.

While Tomasetti and Vogelstein’s first paper led to no less than a few hundred papers written in response, their new study appears to be more soothing to the nerves.

Answers for those who did everything right

“I was concerned about the last article, because it didn’t talk enough about prevention and it left people thinking, ‘Gee you’re just destined to get cancer and you can’t do anything about it,’” said Dr. Otis Brawley, chief medical officer of the American Cancer Society. Brawley, who was not involved in the research said he was “much happier” with the current paper, even if it “doesn’t tell me anything I hadn’t known for the last 20 years.”

“Bert Vogelstein is an incredibly well-respected, well-known cancer biologist who published a paper very similar to this – you might even call it part one of this paper – two years ago,” said Brawley, explaining the original paper caused “quite a stir” because it implied that “almost all cancers were not preventable.”

“And it really upset the anti-smoking people, it upset the folks who are in the nutrition and physical activity for cancer prevention – he really upset the prevention crowd,” said Brawley, who believes the new paper is generally a better explanation of the original theory.

“Keep in mind it’s a mathematical simulation, it’s not a clinical trial, but [Vogelstein is] noting that a certain number of cases are due to replication error, DNA replication error, in normal growth,” said Brawley. “Those are cancers we really cannot do a lot to prevent.”

Brawley described counseling a 47-year old woman who said she’d done everything right: She ate healthy, exercised, didn’t smoke and got yearly mammograms. Despite having a clean mammogram just six months earlier, she was diagnosed with stage 4 breast cancer.

How did this happen to me? she asked Brawley.

The answer is she had a replication error, said Brawley. “And the way you think about replication error is DNA is always being copied throughout your body a million times every day, you know, cells die off and cells are replaced. We have mitosis and an important thing in cell duplication or mitosis is DNA is replicated or copied and the DNA is supposed to be copied exactly and occasionally there’s a misreplication or miscopying.”

Brawley appreciates the fact that Tomasetti and Vogelstein acknowledge the past controversy and make a point in their new paper of addressing prevention and detection.

“I think that we need to have a balance between cancer prevention efforts as well as what I would call wise early detection or wise screening efforts,” said Brawley.

“There’s a tendency in the US to think that every screening test is great. Unfortunately there are screening tests that actually cause more harm than good,” said Brawley.

“In the 1960s and 1970s, we stopped doing chest X-ray screening for lung cancer because, after 20 years of doing it, we finally got around to doing an assessment and we found the death rates were higher in the screened versus the unscreened group,” said Brawley. The reason? When a patient’s chest X-ray was found to be abnormal, the follow-up biopsy might cause a collapsed lung or heart attack, he explained.

“We still have huge debates whether there’s a benefit to prostate cancer screening. There, the benefit might be to a subset of men and not to all men – that’s an unknown, that’s a question mark,” said Brawley.

When it comes to mammography screening, that’s something “all of us believes saves lives – but it’s not perfect,” said Brawley.

“The best studies that we have show that mammography reduces risk of death by 30%,” said Brawley. “That means if you have a group of women who habitually get screened, get good high quality screening, mammography is not going to help 70%.”

According to Vogelstein, the new study is important for two reasons.

“We hope this research offers comfort to the literally millions of patients who have developed cancer but have led near perfect lifestyles,” said Vogelstein. Non-smokers who have avoided the sun, these cancer patients eat healthy diets, exercised and done everything to prevent cancer. “But they still get it,” said Vogelstein.

It’s important, especially for parents of children who have cancer, that people understand the root causes of cancer.

“The first thing someone looking on the web would see is cancer is caused by environment or heredity,” said Vogelstein. When it comes to the parent of a child with cancer, they think they either transmitted a bad gene or exposed their child to an environmental agent that caused disease.

“This causes a tremendous amount of guilt,” said Vogelstein, who is also a pediatrician and has seen such cases. “We don’t need to add guilt to an already tragic situation.”

The second reason the study is important is because cancer will strike about 1.6 million people in the United States this year. “And it will kill 600,000 of us,” said Vogelstein. “We need a completely new strategy.”

He hopes new awareness of these random mutations will inspire many scientists to “devote their efforts to various strategies to limit the damage that these internal enemies do.”

“The first step is simply recognizing these enemies exist,” said Vogelstein.