Many Cancer Types Caused by 'Bad Luck' of Random Mutations

Roxanne Nelson

January 08, 2015

Cancer is an insidious disease that often strikes individuals who lack any type of known risk factors, and new research shows that many cancer types can be chalked up to "bad luck."

Using a statistical model that measured the proportion of cancer incidence across 31 tissue types, researchers from Johns Hopkins University School of Medicine in Baltimore, Maryland, found that 22 cancers, or two thirds of the total reviewed, could be largely explained by the "bad luck" or random mutations that arise during DNA replication in normal, noncancerous stem cells.

The remaining 9 cancer types were more attributable to environmental, lifestyle, and hereditary factors.

Published in Science on January 2, this paper has generated quite a bit of discussion, scrutiny, and opinion pieces, as well as many questions regarding the methods and calculations. Some of the mainstream media have also joined the fray by headlining their stories with titles such as "Most Cancers Caused by Bad Luck," or "Cancer Is Down to Bad Luck" and thus misinterpreting the findings to mean that two thirds of all cancer cases are simply a roll of the dice.

In response to the discussions and questions, study authors Bert Vogelstein, MD, Clayton Professor of Oncology at Johns Hopkins and codirector of the Ludwig Center, and Cristian Tomasetti, PhD, an assistant professor of oncology at the Johns Hopkins School of Medicine and the Bloomberg School of Public Health, issued a statement to shed more light on their research.

"We emphasize that no single factor causes cancer," they write. "Some have misunderstood our research to say that two-thirds of cancer cases are due to bad luck. We want to stress that cancer is caused by a combination of many factors."

Focus on Stem Cell Divisions

In their study, the researchers reviewed the published literature on 31 different types of cancer including those of the lung, thyroid, colon, ovary, pancreas, and skin and then estimated the lifetime risk of developing cancer, and how often stem cells divide in those tissues. Two of the most common cancers, breast and prostate, were excluded from the analysis because of the inability to find reliable stem cell division rates in the scientific literature.

The authors then calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions. The linear correlation equal to 0.804 suggested that 65% of the differences observed in cancer incidence among different tissues could be explained by the total number of stem cell divisions in those tissues.

In their paper, the authors note that some types of tissue develop cancers far more frequently — in fact millions of times more so — than other tissue types. While scientists have recognized this phenomenon for more than 100 years, it has never been explained.

But the current findings now show that organs with a large number of lifetime stem-cell divisions have higher incidences of cancer. In other words, tissues in which stem cells divide frequently, such as the colon, were more likely to develop cancer than those with less frequent stem cell division.

Car Accidents and Cell Divisions

Using the analogy of an automobile accident, the authors note that their results would be "equivalent to showing a high correlation between length of trip and getting into an accident. Regardless of the destination, the longer the trip is, the higher the risk of an accident."

This could be likened to the stem cell divisions and random mutations discussed in the paper, they note. Even with poor road conditions and a car having mechanical difficulties, the length of the trip plays a significant role. Short trips have the lowest risk, while long trips are associated with the highest risk.

That said, two thirds of accidents are not caused solely by the length of the trip because a combination of other factors are at play. "To know what portion of accidents are due to each of these factors, we'd need detailed information about the number of trips to each destination, the condition of each car and the conditions of every road traveled, among other things," say Dr. Vogelstein and Dr Tomasetti. "We do not have such knowledge about trips, and we do not have equivalent information about cancers."

Not Powerless in the Face of Cancer

"In essence, the paper relates the rate of stem cell turnover in different tissues to the frequency with which they develop cancer, and shows something we already knew from other work, that the more cell divisions take place in a tissue the more prone it is to developing cancer," commented Peter Johnson, MD, chief clinician, Cancer Research UK in London.

A lot is known about the relationship between lifestyle and cancer risk for some very common types, including lung, esophagus, breast, and colorectal cancers and melanoma, for example, he told Medscape Medical News. "In general this fits with the findings of the paper — things which cause increased proliferation in tissues or which increase the frequency of mutations lead to more cancers."

He pointed out that it is true that a large proportion of the variation in cancer rates is down to chance, but also that in some cancer types the environmental or lifestyle influences may not have been identified. "But this is not to say that people are powerless in the face of chance, and in fact, quite the reverse," said Dr Johnson.

"We know that adopting a lifestyle which reduces the levels of inflammation in tissues and which reduces their exposure to carcinogenic substances can reduce the risk of cancers across a population, although it is hard to say which particular person will be helped in this way since some of the background risk is due to other factors which we cannot predict," he added.

The research was funded by the Virginia and D. K. Ludwig Fund for Cancer Research, the Lustgarten Foundation for Pancreatic Cancer Research, the Sol Goldman Pancreatic Cancer Research Center, and the National Institutes of Health's National Cancer Institute.

Science. 2015;347:78-81. Abstract


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.