Aspirin's Benefit in Preventing Colon Cancer Depends on DNA

By Sharon Begley

April 24, 2014

NEW YORK (Reuters) - Two decades after scientists discovered that aspirin might reduce the risk of colorectal cancer, a new study finds that it has that benefit almost exclusively in people with genes that produce high levels of a particular enzyme.

Those whose DNA produces low levels of the enzyme known as 15-PGDH benefit hardly at all, scientists reported in the journal Science Translational Medicine, April 23.

"If you have low levels of (the enzyme), taking aspirin to reduce your colon cancer risk is probably not helping you," said Dr. Sanford Markowitz, professor of cancer genetics at Case Western Reserve School of Medicine in Cleveland and co-leader of the study. "But people with higher levels are getting a bang for the buck: The combination of high enzyme levels plus taking aspirin really seems to be the key to measurably reducing colon cancer risk."

Identifying who can cut their risk of colorectal cancer, which the American Cancer Society projects will kill 50,000 people in the United States this year, by taking aspirin is especially important because the drug poses a significant risk of ulcers and gastrointestinal bleeding, which can be fatal.

Because the gastrointestinal dangers are too great to justify the uncertain benefits, the U.S. Preventive Services Task Force, which advises the government, recommends against the use of aspirin to prevent colorectal cancer in the general population.

"But if you could tailor prevention to people who have both a high risk of the disease and the greatest likelihood of benefiting from it, that could change the balance," said Dr. Andrew Chan of Massachusetts General Hospital in Boston, who co-led the study.


Both the 15-PGDH enzyme and aspirin target prostaglandins. These molecules promote the growth of colon cells and also inflammation; both increase the risk of cancer.

Aspirin inhibits production of prostaglandins. The enzyme chews them up. Result: lower levels of cancer-promoting molecules.

Chan and his team mined the long-running Nurses' Health Study and the Health Professionals Follow-Up Study, both based at Harvard School of Public Health and sister institutions. Among the 127,865 participants were 270 cases of colorectal cancer for which the Boston team had records of aspirin use.

Markowitz's team them determined the levels of the genetic material that produces 15-PGDH in the patients' colons.

In people whose DNA produces high levels of the enzyme, regular aspirin use reduced the risk of colorectal cancer by half, and possibly by as much as two-thirds. In people with lower levels, aspirin use reduced risk by only 10%, and may have increased it.

"That represents a clean yes-or-no about who would benefit from aspirin," Markowitz said.

In any research that examines what people do on their own rather than what they're assigned to do as part of a study - in this case, take aspirin or not - it's always possible that something other than the factor scientists focused on caused the different health effects. Chan and his team are confident they eliminated smoking, eating meat, drinking alcohol and other lifestyle factors as explanations for the different colon-cancer rates, leaving only aspirin and enzyme levels.

"But there is always a chance that something else is going on and we don't know it, like all the high-PGDH people were also marathon runners" or had some other trait that slashed their cancer risk, said Markowitz, who is also a medical oncologist at University Hospitals Case Medical Center.

About half the U.S. population produces high levels of the enzyme in the colon, and half produces low levels. Neither blood nor genetic testing is reliable for the enzyme, Markowitz said, but its levels can be measured via colon biopsy, which can be done during a routine colonoscopy.

The people most likely to benefit from aspirin, in terms of colorectal cancer, are those with a family history of the disease or a personal history of certain polyps, and should have screening colonoscopies anyway, Markowitz pointed out.

An earlier study, in lab mice, found that 15-PGDH seemed to boost the ability of celecoxib (Celebrex) to prevent colon tumors. But with low 15-PGDH levels, the drug had no such benefit. It is likely, Markowitz said, that in people, too, celecoxib's effect on the risk of colon cancer depends on 15-PGDH levels.


Sci Transl Med 2014.


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