How to Tell Whether a Cancer Is Caused by Plain Bad Luck

Cancer is caused by a combination of bad luck and exposure to carcinogens such as tobacco, ultraviolet light or sometimes viruses. The question of the relative contribution of luck has been debated for years.

If a cancer is caused by toxic exposures, then public health efforts should focus on strategies to prevent them. If a cancer is the result of random mutations, little can be done to prevent it, and efforts might instead focus on early detection and treatment.

A team of researchers has addressed the ongoing controversy with a degree of mathematical exactitude. A method inspired by evolutionary models of natural selection in wild populations was devised by Jeffrey Townsend of Yale University and others.

There are many genetic changes inside a tumor, but only a small subset of them. The rest are harmless. The researchers were able to estimate the proportion of driving mutations caused by carcinogens and accidental alterations in DNA that occur during normal cell division using previous knowledge about the specific patterns caused by exposure to tobacco smoke or UV light.

The researchers used this method to investigate the causes of point mutations in 24 major cancer types. They were able to estimate how many cancer-driving genes were linked to each type.

James De says the study is a step forward because it allows a better assessment of the particular contribution of the agent.

There have been a lot of sidetracks taken over the years, according to cancer researcher and oncologist Rameen Beroukhim of the Dana-Farber Cancer Institute, who was not involved with the new study. It has been important to understand the signatures of different processes, but Beroukhim and his colleagues are interested in the small subset of mutations that are causing the cancer to grow.

It has been difficult to pin down the causes of a cancer. The discussion has focused on risk factors that could have contributed to the development of a tumor. One of the most difficult questions that patients and doctors struggle with after a cancer diagnosis is how to pin down the causes of the driving mutations in a given patient's tumor.

The study only looked at single letters of the DNA, not large rearrangements of chromosomes or increases in copies of a gene that are frequently found in cells as they become cancer. The researchers didn't have a way to quantify the effect of the large changes in their evolutionary models.

In some cancers, one out of every 10 million nucleotides undergoes a point mutations, but one of every three is involved in chromosomal rearrangements or increases in copy numbers, Beroukhim says. It is not known how much these big rearrangements contribute to cancer growth.

The findings are limited because they don't take into account the large changes in the genome. It is possible that the percentage of point mutations caused by environmental exposures is the same for other types of mutations, so the conclusions would largely be the same. We will learn in the future, but this is the first way of doing it.

Figuring out causality in cancer is not easy. If a cancer-drivingmutation does not have the signature of a carcinogen exposure, that does not mean that the carcinogen did not contribute to the cancer, says DeGregori. He argues that the environmental exposure may have been a factor in the development of the cancer. Smoking changes the environment in a smoker's lung, so a cell inside that lung would behave differently than a cell in a nonsmoker's lung. The environment of a cell will affect its behavior.

In the same way, if you drink alcohol, exercise or obese, you may not directly cause a certain type of cancer, but if you change the metabolism in the body, you may change the risk of cancer as well. Future work needs to incorporate this larger context. As more cancer genomes are available, future work will extend to more cancer types.

This method could provide insights into the age-old problem of cancer resistance to treatment, in which a tumor will respond to treatment but come back after some time. Many of the drugs are mutagenic. The hope is that cancer cells will be more damaged by the mutations than healthy cells. The tumors may evolve resistance to treatment. They used their evolutionary model to pin down which tumors are resistant to certain treatments and which combinations or sequence of treatments to avoid.

The method's ability to address what causes cancer at the level of individual patients means that it could be very useful in legal cases. It's hard to prove that a group of cancer cases in a community were caused by pollution or a toxic waste site nearby. This method of looking at the tumors of cancer patients could have implications for legal liability.

It would have been useful to be able to say the signature of tobacco smoking on all of these patients.