8 January 2015

Some cancers caused by bad luck - early detection is key

Source: Johns Hopkins Medicine. Credit: C Tomasetti, B Vogelstein and Illustrator Elizabeth Cook, Johns Hopkins. 

Scientists from the Johns Hopkins Kimmel Cancer Center have found that two-thirds of adult cancer can be explained primarily by “bad luck,” or random mutations that occur in the genes that can drive cancer growth, while the remaining third are due to environmental factors and inherited genes. The authors of the paper Variation in cancer risk among tissues can be explained by the number of stem cell divisions, published January 2 in Science, stress however in a FAQ dated January 7 hat this is not the same as saying that two-thirds of all cancers are caused by bad luck as luck may have a varying influence in any particular cancer.

In the FAQ,  Dr Bert Vogelstein, a medical doctor who is 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, and Dr Cristian Tomasetti, doctor of philosphy who is a Biomathematician and also Assistant Professor of oncology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health, describe what happens with the analogy of experiencing a car accident.

"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 travelled.  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." 

“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,” commented Dr Vogelstein in the original January 1 statement. 

Dr 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 scientists charted how often stem cells divide in 31 body tissues and compared these rates with the lifetime risks of cancer in the same tissues among Americans. Tomasetti and Vogelstein then found that 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. This does not necessarily mean that one causes the other, but the likelihood is there.

“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 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.

To analyse the correlation further and see if they could establish causation, the scientists looked for ways to prove the relationship between stem cells dividing and 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, rather than cancer being associated with the colon itself.
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.

Both scientists say that the research predicts that more cancers will appear in the future simply because ageing 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," they said in the FAQ.

Read the study in Science here. Read the FAQ here.

*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.

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).