Abstract
In a new study, scientists have quantified the somatic mutation theory of cancer by comparing stem-cell division rates in different tumors with the lifetime risk of cancer in corresponding tissues. They found a strong correlation, suggesting that two thirds of the variation in cancer risk in these tissues can be explained by random mutations that occur as stem cells divide.
As cells replicate, DNA copies itself imperfectly. The more frequently cells divide, the greater is their risk of accumulating random mutations that can lead to malignant transformation.
The contribution of these random mutations to cancer was recently quantified by two researchers at the Johns Hopkins School of Medicine in Baltimore, MD: biomathematician Cristian Tomasetti, PhD, and Bert Vogelstein, MD, co-directors of the Ludwig Center for Cancer Genetics and Therapeutics. They focused on stem cells, which endlessly renew themselves and are therefore especially susceptible to genetic errors.
Using published data, Tomasetti and Vogelstein plotted the number of stem-cell divisions in 31 tumor types against the lifetime risk of cancer in the same tissues among Americans; they found a striking correlation. Because reliable stem-cell division rates are not available in the literature for tissues associated with two common cancers—breast and prostate—those were not analyzed.
The researchers then calculated that approximately two thirds (65%) of the variation in cancer risk across these tissues could be explained by stem-cell divisions. For instance, patients with familial adenomatous polyposis are about 30 times more likely to develop colorectal than duodenal cancer; Tomasetti and Vogelstein suggest in their study that this relationship exists because colon stem cells divide approximately 150 times more frequently than those in the duodenum. Further statistical analyses suggested that the 31 tumor types lie along a continuum from “replicative,” strongly driven by random mutations, to “deterministic,” in which known environmental or genetic factors come into play.
“We think that a replicative component should be added to the duet of environment and heredity,” Vogelstein says. “This trio is responsible for all of the mutations that occur in cancer.”
“This study shows a distinct relationship between stem-cell divisions and cancer risk,” says Timothy Rebbeck, PhD, a cancer epidemiologist at the University of Pennsylvania in Philadelphia. “I'm a little surprised at the correlation strength, but it's interesting and another puzzle piece that tells us something about the nature of cancer.”
“Our theory predicts that in many cancers, the majority of mutations are replicative, while in others, environmentally induced mutations are key,” Vogelstein says. “The stochastic effects of DNA replication are beyond control, but other factors are not.”
Rebbeck gives the example of smoking, which increases the risk of lung cancer. “There may also be some randomness at play,” he says, “but that doesn't mean we can't prevent this disease through lifestyle changes.” Vogelstein adds that for cancers driven substantially by replicative mutations, “early detection and treatment should be the major focus.”
More cancers will likely appear in the future “simply because aging increases the number of stem-cell divisions,” Vogelstein says. “Research on primary and secondary prevention, treatment, and disease biology is more important than ever.”