Johns Hopkins Medicine is gratified by the responses and discussion generated by Cristian Tomasetti and Bert Vogelstein’s research paper, “Variation in cancer risk among tissues can be explained by the number of stem cell divisions,” published in Science on Jan. 2, 2015, and a news release describing the work, “Bad Luck of Random Mutations Plays Predominant Role in Cancer, Study Shows.” Cancer is driven by a number of factors and causes, and concepts related to calculating risk are complex and often the subject of debate. To facilitate the ongoing discussion, and to address the many thoughtful questions their research stimulated, the two scientists have provided the following answers to frequently asked questions.
Is there an analogy that can help put the results of your research in perspective?
Getting cancer could be compared to getting into a car accident. Our 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.
The road conditions on the way to the destination could be likened to the environmental factors in cancer. Worse conditions would be associated with a higher the risk of an accident.
The mechanical condition of the car is a metaphor for the inherited genetic factors. The numbers of mechanical problems in the car—bad brakes, worn tires, etc.—increase the risk of an accident. Think of these mechanical problems as inherited genetic mutations. With each mechanical defect, the risk of an accident increases. Similarly, the amount of inherited genetic mutations is among the factors that contribute to cancer risk.
Now, consider the length of the trip. This could be likened to the stem cell divisions and random mutations we discuss in our paper. Even with bad road conditions and driving a car in disrepair, the length of the trip plays a significant role. An extremely short trip has an accident risk close to zero. Regardless of road and car conditions, the probability of an accident occurring increases with distance traveled. Short trips have the lowest risk, while long trips are associated with the highest risk.
Using this analogy, we would estimate that two-thirds of the risk of getting into an accident is attributable to the length of the trip. The rest of the risk comes from bad cars, bad roads and other factors. In terms of cancer, we calculate that two-thirds of the variation is attributable to the random mutations that occur in stem cell divisions throughout a person’s lifetime, while the remaining risk is associated with environmental factors and inherited gene mutations.
Can your results help explain what causes cancer?
We emphasize that no single factor causes cancer. 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. Referring back to our car analogy, we can’t say that two-thirds of accidents are caused solely by the length of the trip. Every accident is caused by some combination of road conditions, car conditions, length of the trip and other factors. On some trips, the length of the trip may be the major contributing factor, while in other accidents, bad roads may be the major factor. 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. We do not have such knowledge about trips, and we do not have equivalent information about cancers.
How do these random mutations relate to cancer prevention?
Some risk factors may be outside of our control, but others are not. The fact that much of the risk of traveling by car is due simply to the trip distance doesn't mean that accidents cannot be prevented. Distance is one factor, but even if the distance of a trip cannot be changed, traveling can be made safer by driving well-maintained vehicles, using safety devices, such as seatbelts and airbags, and choosing a particular route. Controlling the risk of accidents associated with bad cars and bad roads prevents accidents and reduces overall risk.
In the same way, we can prevent many cancers. Like car accidents, cancer is caused by a combination of factors—random DNA changes made during stem cell divisions that are not within our control, environmental exposures and inherited gene mutations. As a result, there are many opportunities for cancer prevention. The best way to prevent some cancer types is by eliminating environmental factors and by changing lifestyles. This is known as primary prevention. Quitting smoking is one valuable example of primary prevention.
The best way to prevent deaths from other cancer types is to detect them and treat them early, while they are still curable. This is called secondary prevention. One of the important aspects of our research was to further highlight cancer types that could be best impacted by primary prevention versus secondary prevention.
What do you say to those who have been discouraged by your findings?
We are aware that the idea that a major contributing factor to cancer is beyond anyone's control can be jarring. This doesn't mean that cancer research should be stalled in any way. Quite the opposite—our research emphasizes the likelihood that more cancers will appear in the future simply because aging increases the number of stem cell divisions. Research on primary and secondary prevention, cancer treatment, and the biology of the disease is more important than ever.
By the same token, many people have found relief in this research. Cancer has a long history of stigmatization. Patients and family members frequently blame themselves, believing there was something they could have done to prevent their or their family member’s cancer. We have heard from many of these families and are pleased that our analysis could bring comfort and even lift the burden of guilt in those who have suffered the physical and emotional consequences of cancer.
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Scientists from the Johns Hopkins Kimmel Cancer Center have created a statistical model that measures the proportion of cancer incidence, across many tissue types, caused mainly by random mutations that occur when stem cells divide. By their measure, two-thirds of adult cancer incidence across tissues can be explained primarily by "bad luck," when these random mutations occur in genes that can drive cancer growth, while the remaining third are due to environmental factors and inherited genes.
"All cancers are caused by a combination of bad luck, the environment and heredity, and we've created a model that may help quantify how much of these three factors contribute to cancer development," says Bert Vogelstein, M.D., the Clayton Professor of Oncology at the Johns Hopkins University School of Medicine, co-director of the Ludwig Center at Johns Hopkins and an investigator at the Howard Hughes Medical Institute.
"Cancer-free longevity in people exposed to cancer-causing agents, such as tobacco, is often attributed to their 'good genes,' but the truth is that most of them simply had good luck," adds Vogelstein, who cautions that poor lifestyles can add to the bad luck factor in the development of cancer.
The implications of their model range from altering public perception about cancer risk factors to the funding of cancer research, they say. "If two-thirds of cancer incidence across tissues is explained by random DNA mutations that occur when stem cells divide, then changing our lifestyle and habits will be a huge help in preventing certain cancers, but this may not be as effective for a variety of others," says biomathematician Cristian Tomasetti, Ph.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health. "We should focus more resources on finding ways to detect such cancers at early, curable stages," he adds.
In a report on the statistical findings, published Jan. 2 in Science, Tomasetti and Vogelstein say they came to their conclusions by searching the scientific literature for information on the cumulative total number of divisions of stem cells among 31 tissue types during an average individual's lifetime. Stem cells "self-renew," thus repopulating cells that die off in a specific organ.
It was well-known, Vogelstein notes, that cancer arises when tissue-specific stem cells make random mistakes, or mutations, when one chemical letter in DNA is incorrectly swapped for another during the replication process in cell division. The more these mutations accumulate, the higher the risk that cells will grow unchecked, a hallmark of cancer. The actual contribution of these random mistakes to cancer incidence, in comparison to the contribution of hereditary or environmental factors, was not previously known, says Vogelstein.
To sort out the role of such random mutations in cancer risk, the Johns Hopkins scientists charted the number of stem cell divisions in 31 tissues and compared these rates with the lifetime risks of cancer in the same tissues among Americans. From this so-called data scatterplot, Tomasetti and Vogelstein determined the correlation between the total number of stem cell divisions and cancer risk to be 0.804. Mathematically, the closer this value is to one, the more stem cell divisions and cancer risk are correlated.
"Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue," says Vogelstein. One example, he says, is in colon tissue, which undergoes four times more stem cell divisions than small intestine tissue in humans. Likewise, colon cancer is much more prevalent than small intestinal cancer.
"You could argue that the colon is exposed to more environmental factors than the small intestine, which increases the potential rate of acquired mutations," says Tomasetti. However, the scientists saw the opposite finding in mouse colons, which had a lower number of stem cell divisions than in their small intestines, and, in mice, cancer incidence is lower in the colon than in the small intestine. They say this supports the key role of the total number of stem cell divisions in the development of cancer.
Using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65 percent.
Finally, the research duo classified the types of cancers they studied into two groups. They statistically calculated which cancer types had an incidence predicted by the number of stem cell divisions and which had higher incidence. They found that 22 cancer types could be largely explained by the "bad luck" factor of random DNA mutations during cell division. The other nine cancer types had incidences higher than predicted by "bad luck" and were presumably due to a combination of bad luck plus environmental or inherited factors.
"We found that the types of cancer that had higher risk than predicted by the number of stem cell divisions were precisely the ones you'd expect, including lung cancer, which is linked to smoking; skin cancer, linked to sun exposure; and forms of cancers associated with hereditary syndromes," says Vogelstein.
"This study shows that you can add to your risk of getting cancers by smoking or other poor lifestyle factors. However, many forms of cancer are due largely to the bad luck of acquiring a mutation in a cancer driver gene regardless of lifestyle and heredity factors. The best way to eradicate these cancers will be through early detection, when they are still curable by surgery," adds Vogelstein.
The scientists note that some cancers, such as breast and prostate cancer, were not included in the report because of their inability to find reliable stem cell division rates in the scientific literature. They hope that other scientists will help refine their statistical model by finding more precise stem cell division rates.
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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 (grants P30-CA006973, R37-CA43460, RO1-CA57345 and P50-CA62924).
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