DRIVING MUTATIONS MOSTLY DUE TO BAD LUCK?

Again the question asserts itself — are many cancers simply due to "bad luck"?

Two years ago, the media went into a tailspin over a research article in Science that suggested that many cancer types can be chalked up to random mutations, or simply "bad luck."

It led to quite a bit of discussion, as well as many questions regarding the underlying methods and calculations.

The same authors have now published a second study that supports their earlier conclusions.

For the new study, also published in Science, the researchers analyzed genome sequencing and epidemiologic data from 32 cancer types and concluded that DNA replication errors (R) are responsible for about two thirds of the mutations in human cancers.

This is a "complete paradigm shift in how we think of cancer," coauthor Cristian Tomasetti, PhD, assistant professor of biostatistics at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health, in Baltimore, Maryland, said during a press briefing. "The 65% says that the R component is here to stay, and it is a major one."

It suggests that 65% of cancer is due to chance, or "bad luck" – which is the same message that caused such an uproar when it was initially suggested by the first study.

An introduction to the article helps to explain why – "most textbooks attribute cancer-causing mutations to two major sources: inherited and environmental factors." These new studies highlight the prominent role of R mutations in cancer. These mutations arise from a third source: unavoidable errors associated with DNA replication.

At the press briefing, Dr Tomasettie and coauthor Bert Vogelstein, MD, codirector of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center, went on to reconcile the two different ways of thinking. They emphasized that their findings are consistent with epidemiologic studies suggesting that about 40% of cancers can be prevented by changes in the environment.

These findings do not negate the importance of factors such as diet, exercise, and smoking, which contribute to cancer development, they said.

"Mutations are unavoidable, and cancers to some extent are unavoidable," Dr Vogelstein told journalists. "It doesn't mean that we should add to that by smoking or exposure to other noxious influences."

However, many people will develop cancers because of these random DNA copying errors, regardless of environmental factors.

Differences in the Articles

One the main differences between the current article and the 2015 study is the inclusion of breast and prostate cancer in the analysis, explained Dr Tomasetti, "which are two very important cancer types with a very high incidence."

Another important issue that was addressed, he noted, was that the 2015 article was conducted in the United States. "It left behind the question: If there is a well- known variation in cancer incidence, how would the result change if we did it in another country?" he said. "If environmental factors were important, then in another country, the correlation may be completely different.

The new study analyzed the relationship between the number of normal stem cell divisions and the risk for 17 cancer types in 69 different countries. It showed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of any environmental factors.

"The correlation is essentially what we presented for the United States, and I think that is a very important step forward," Dr Tomasetti commented.

But the most important point of this new article is that it adds clarifies the original one. "What this paper shows is that for the very first time, someone has looked at proportions of mutations within each cancer type and assigned them to three factors," Dr Tomasetti said. "This is a completely new result compared to our previous one, and a really fundamental one."

In the earlier study, Dr Tomasetti and Dr Vogelstein reported that random errors that occur during DNA replication in normal stem cells are a major contributing factor in cancer development.

"Remarkably," they wrote, "this 'bad luck' component explains a far greater number of cancers than do hereditary and environmental factors."

Thus, in addition to environmental factors and heredity, they hypothesized that a third source — the "R" factor, or mutations due to the random mistakes made during normal DNA replication ― can explain why cancers are more common in some tissues.

In the new study, they switched gears and attempted to evaluate the fraction of mutations in cancer that are due to these DNA copying errors.

The authors studied the mutations that drive abnormal cell growth among 32 cancer types. They subsequently developed a mathematical model using DNA sequencing data from the Cancer Genome Atlas and epidemiologic data from the Cancer Research UK database.

Their findings demonstrate that two or more critical gene mutations are usually required before a cancer develops. These mutations can be caused by random DNA copying errors, environmental factors, and/or heredity.

They also found varying contributions of random errors and environmental/hereditary factors in the different types of cancer that were studied.

For example, in pancreatic cancers, their mathematical model showed that when critical mutations are added together, 77% appear to be due to random DNA copying errors. In contrast, only 18% could be attributed to environmental factors, and 5% to heredity.

For cancers of the prostate, brain, or bone, they report that more than 95% of mutations are caused by random copying errors.

The scenario for lung cancer is different. In this cancer type, 65% of all mutations can be attributed to environmental factors, primarily smoking. Only 35% are due to DNA copying errors, and heredity is thus far not known to have any role in this disease.

The authors estimate that fully two thirds (66%) of the 32 cancers studied were the result of copying errors, whereas only 29% could be attributed to lifestyle or environmental factors, and 5% to heredity.

The Enemy Within

Dr Vogelstein summed up their research using an analogy of a country being invaded by hostile forces. "If enemies are outside of our borders, it is obvious how to prevent them from coming in. You lock the borders.

"But suppose a lot of our enemies are already inside our country," he continued. 

Then the border locking strategy doesn't work. We need a completely new strategy, and up until now, there has been very little attention to the enemies that are already here."

So the question is, what do we do with the mutations that have nothing to do with environmental factors and that are "already here"?

"We know from this research that most of the enemies are already inside of us, they are already here," said Dr Vogelstein. "We hope that one of the implications of this research is that it will inspire scientists to recognize this fact and then devote their efforts to various strategies to limit the damage of these internal enemies."

Need for Mathematical Understanding

In an accompanying editorial, Martin Nowak, PhD, Harvard University, Boston, Massachusetts, and Bartlomiej Waclaw PhD, from the University of Edinburgh, United Kingdom, reiterate that in the current study, the authors demonstrate that a large portion of the variation in cancer risk "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," they write.

The earlier analysis by these authors has already stimulated much discussion, and they note that the current findings will undoubtedly cause that conversation to continue.

But importantly, the "findings point to a clear need for a precise mathematical understanding of cancer," write Dr Nowak and Dr Waclaw. "It will take many years to answer in detail the interesting and exciting questions that have been raised."

"Reductionist Approach to Complex Problem"

In a news article in Science concerning the new study, staff writer Jennifer Couzin-Frankel summarizes the main finding as follows: "Ultimately, its authors conclude, across 32 cancer types, 66% of cancer-promoting mutations arise randomly during cell division in various organs throughout life, 29% trace to environmental causes, and 5% are inherited."

The researchers estimate that 66% of mutations driving cancer were due to "bad luck," she writes. But they emphasized, as they had previously, that that does not mean two thirds of cancer cases are from those "bad luck" mutations.

"Of course these are estimates," Dr Tomasetti said at the press conference. "It's the best that can be done today. It's a paradigm shift in how we think about cancer."

However, Couzin-Frankel also writes that "many researchers Science spoke with took issue with the authors' hard numbers for various reasons." She reported on their reactions.

"[The authors] make a point that heredity is associated with a certain percentage of cancer, and environment is associated with a certain percent, and this is probably true," says Anne McTiernan, MD, PhD, a physician and epidemiologist at the Fred Hutchinson Cancer Research Center, Seattle, Washington. "But then to assume that the rest is because of stem cell divisions and chance...we just don't know."

"I think why people struggle with this, it's a very reductionist approach to a complex problem," says Prof Richard Gilbertson, a pediatric oncologist and cancer biologist at the University of Cambridge in the United Kingdom. "Cancer is far more complex than mutations and proliferation," Dr Gilberton suggests. This article, he and others say, seeks to distill it down to those two drivers to the exclusion of everything else.

"The whole idea of viewing cancer as a whole is pretty alien to us, the causes of different types are so different," says Noel Weiss, DPH, an epidemiologist at the Fred Hutchinson Cancer Research Center. "What seems random today will not seem so random in the future."