How to tell if cancer is caused by pure bad luck

Cancer results from a combination of spontaneous mutations that occur with age – just call it “bad luck” – and environmental exposures to carcinogens such as tobacco, ultraviolet light or sometimes viruses. But the question of the relative contribution of luck – compared to more explicit causes – has been the subject of vigorous debate for years.

The distinction is important because of the implications for cancer prevention: if cancer is primarily caused by toxic exposures, public health efforts must focus on strategies to prevent those exposures. But if a cancer is primarily the result of random mutations, then little can be done to prevent it, and efforts may instead focus on early detection and treatment.

Now, a team of researchers has tackled this ongoing controversy with a degree of mathematical accuracy. Biostatistician and evolutionary biologist Jeffrey Townsend and Vincent Cannataro of Emmanuel College and Jeffrey Mandell of Yale devised a method inspired by evolutionary patterns of natural selection in wild populations to quantify the amount of each so-called point mutation, or change to a single letter of DNA in a tumor helps stimulate its growth.

Inside a tumor there are usually many genetic mutations, but only a small subset of them “drives” the cancerous growth. The others are harmless “passenger” mutations. Using previous knowledge of specific mutational patterns caused by exposures to carcinogens such as tobacco smoke or UV radiation, the researchers were able to estimate what proportion of motor mutations were caused by carcinogens and what proportion resulted from accidental DNA alterations that occur during normal cell division.

In the study, published in Molecular biology and evolution on April 26, researchers used this method to study the causes of point mutations in 24 major cancer types. For each type, they were able to estimate the number of carcinogenic mutations linked to “bad luck”. Confirming epidemiological studies, they found that melanomas and cancers of the lung, bladder and cervix are largely attributable to exposure to carcinogens such as UV rays and tobacco, while Brain and spinal cord tumors called gliomas and prostate tumors called adenocarcinomas are primarily the result of intrinsic mutations that accumulate with age.

The study “is a step forward because it allows a better assessment of the particular contribution of the agent – smoking, UV, etc. – to the real motor mutations”, says James DeGregori, cancer researcher at the faculty. of Medicine from the University of Colorado. , who did not participate in the study. “Let’s say you have lung cancer with five motor mutations – you can say, ‘These three clearly have the signature of smoking, so they were directly caused by smoking.'”

“There have been a lot of detours over the years,” says cancer researcher and oncologist Rameen Beroukhim of the Dana-Farber Cancer Institute, who was not involved in the new study because people assumed the mutated genes frequently in a given type of cancer were to contribute to cancer development, only to find that these mutations were just transients. Understanding the signatures of different mutational processes has been important, but therapeutically what interests Beroukhim and his colleagues is the small subset of mutations that cause cancer to grow.

For this reason, it has been difficult to pinpoint the definitive causes of any given cancer. And so far, the discussion has focused on risk factors – estimated against population averages – that could have contributed to the development of a tumour. Townsend says his team’s new approach can be used to identify the immediate causes of motor mutations in a given patient’s tumor and thus provide a more precise answer to one of the most difficult questions that patients and physicians face. Struggle After Cancer Diagnosis: “Why Me?”

A caveat of the study is that the researchers focused only on mutations in the single letters, or nucleotides, of DNA, not large chromosome rearrangements or increases in the number of copies of DNA. a gene that frequently occur in cells when they become cancerous. The reason is that the researchers had no way to quantify the selective effect of these large mutations in their evolutionary models, although they are currently working on methods to address this issue.

These large mutations are not insignificant in the genomes of cancer cells: in some cancers, one in 10 million nucleotides undergoes a point mutation, but one in three is involved in chromosomal rearrangements or an increase in copy number, Beroukhim explains. Yet it is unclear to what extent these large rearrangements contribute to cancer growth, as they have yet to be quantified for individual cancers.

Townsend acknowledges that the results are limited because they don’t account for these important changes in the genome. It’s possible, he says, that the percentage of point mutations caused by environmental exposures, as opposed to intrinsic factors, is approximately the same for these other types of mutations, so the conclusions would be largely the same. But this hypothesis still needs to be confirmed. “We’ll learn in the future, but this is our first way to do it,” says Townsend.

Moreover, determining causation in cancer remains a complex task. If a cancer-causing mutation does not have the signature of exposure to a carcinogen, this does not mean that the carcinogen did not contribute to cancer; that means he didn’t contribute to that mutation, DeGregori points out. Environmental exposure may have been indirectly responsible for promoting cancer development by altering the environment of the mutated cell, he argues. For example, smoking changes the environment in a smoker’s lung, such that a mutated cell inside that lung would behave differently from the same cell in the lung of a healthy non-smoker. The environment of a cell will influence its behavior and its ability to proliferate.

Townsend agrees that this context is important: similarly, obesity, exercise, or alcohol consumption may not directly cause (or prevent) mutations, but these factors alter the metabolic environment in the body and also modify the risk of cancer. Future work will need to integrate this broader context. Future work will also expand to more cancer types as more cancer genomes are sequenced and become available.

Despite these limitations, this new method could provide insight into the age-old problem of cancer resistance to treatment: often, a tumor initially responds to treatment but reappears after a while. Indeed, many chemotherapies themselves are mutagenic. The hope is that the mutations will be more damaging to cancer cells, which often lack good DNA repair mechanisms, than to healthy cells. But some of these mutations caused by the treatment can allow the tumor to develop resistance to the treatment. Townsend and his colleagues recently used their evolutionary model to determine exactly which mutations caused by a treatment in a given tumor are responsible for resistance to that treatment, thus indicating which combinations or sequences of treatments to use or avoid.

The method’s ability to address the causes of cancer at the individual patient level, which was not possible before, means it could be extremely useful in court cases, the researchers say. For example, it is usually very difficult to prove that a cluster of cancer cases in a community were caused by exposure to pollution or a nearby toxic waste site. But using this method to examine the tumors of cancer patients could establish causal links between the exposure and a specific patient’s tumor, which could have implications for legal liability.

“If this had been available at the time the tobacco lawsuits were ongoing, it would have been incredibly helpful, to be able to say, ‘Here is the signature of smoking on all the tumors in these patients; you can’t say it’s just a side effect,” says Townsend. “It’s nice to have a direct link between the tumor itself and the mutagens that caused it.”

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