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Science: Random Mutations Explain Cancer Incidence in Many Tissues

Researchers have been trying to figure out why cancer develops in some human tissues, such as colon tissue, far more frequently than in others, such as bone. Now, a new study suggests that random mutations that occur in healthy, dividing stem cells can explain much of this dramatic variation, with hereditary or environmental factors adding their important effects.

News, December 31, 2014 Bad Luck Cancer

Two-thirds of the variation in cancer incidence can be explained by the 'bad luck' of mutations that occur during stem cell division. | Elizabeth Cook

Cristian Tomasetti and Bert Vogelstein of the Johns Hopkins University uncovered a strong, positive correlation between the number of normal stem cell divisions in a tissue during one's lifetime and the incidence of cancer in that particular tissue. And this surprising discovery — that replicative chance, or "bad luck," plays such a significant role in cancer incidence among various tissues — might allow researchers to design more effective prevention strategies for different cancer types.

Tomasetti and Vogelstein had originally planned to remove this "bad luck" from the equation and focus on the contribution of hereditary and environmental factors to cancer incidence. Instead, they found that only one-third of the variation in cancer incidence among tissues can be attributed to inherited predisposition and the environment.

The researchers' complete findings are published in the 2 January issue of Science.

"While there are, of course, many cancers where primary prevention has huge positive effects — such as vaccines against infectious agents, quitting smoking, or other altered lifestyles — our analysis seems to indicate that, for many other cancers, primary prevention may not be as effective overall," explained Tomasetti.

"However, this does not imply at all that there is not much we can do to prevent those cancers," he said. "It just highlights the importance of secondary prevention, such as early detection. We should probably focus more resources and research on finding ways to detect cancer at early, curable stages."

To reach their conclusions, Tomasetti and Vogelstein analyzed published data on stem cell divisions in 31 different human tissues and compared those data to the lifetime incidence of cancer in those tissues.

"In many tissues, there is a hierarchy of cells: some live for a long time and keep a tissue in equilibrium by producing other, more specialized cells, which only live for a few days or weeks," said Tomasetti. "We thought it was important to focus only on the long-lived type of cells — the stem cells — that will carry over mistakes if and when they are made, by transferring them to their progeny."

"But it's not just about how many stem cells there are," he continued. "It's also about how many times they divide. When you combine these values, you can estimate how many of these 'risky' mutation events happen."

"So for every one of those 31 tissues we had to estimate how many stem cells there were, and then how many times in a lifetime of a person that they undergo division."

The large intestine or colon, for instance, has a higher rate of stem cell division than the small intestine, the researchers noted, which may explain why the incidence of colon cancer is greater than the incidence of cancer in the small intestine.

It seems that the majority of the variation in cancer incidence among tissues is simply due to bad luck, or random mutations that occur when healthy stem cells replicate their DNA during division, they say. But genes and the environment still have a huge effect on cancer incidence, especially for some inherited cancers such as the colon cancer familial adenomatous polyposis or lung cancer and its well-known link to cigarette smoke exposure.

Tomasetti and Vogelstein compare the difference to a road trip in bad weather: "If I drive to Chicago, the risk of having an accident is higher than if I was just going to the grocery store, simply due to the number of miles traveled, and this represents the random 'luck' component: The more stem cell divisions a tissue has the more the risk of getting cancer," Tomasetti said.

"Now, if it's snowing on my way to Chicago, then my risk of an accident becomes much greater since I'm doing it in bad weather. And that, for example, could represent an environmental factor, such as smoking. In fact, this Chicago trip may be even more risky than a much longer trip with perfect weather conditions."

"This work strongly highlights the importance for early detection to be a major focus in our fight against cancer, particularly for tissues in which cancer incidence appears to be mostly random," Tomasetti said.