Gene Mutation and Excess Ovulation: Recipe for Cancer?

Researchers have pinpointed a biological flaw that appears to explain why women who ovulate frequently are at higher risk for ovarian cancer. The findings, published in the July issue of the Journal of the National Cancer Institute, suggest that women who have taken birth control pills, been pregnant, or have breast-fed--all of which suppress ovulation--gain some measure of protection from ovarian cancer, which kills nearly 15,000 women in the United States each year.

Since the early 1970s, medical researchers have known that the more often a woman ovulates, the higher her ovarian cancer risk. In addition, recent evidence has shown that about 50% of women with ovarian tumors have spontaneous mutations in a key tumor-suppression gene, p53. Now, oncologist Andrew Berchuck and his colleagues at Duke University have tied these two findings together. They screened for p53 mutations in 197 ovarian cancer patients, aged 20 to 54, and 3363 controls in an ongoing trial called the Cancer and Steroid Hormone study. They also tallied each woman's number of lifetime ovulatory cycles (LOCs) and classified them according to a low number of LOCs (less than 235), medium (235 to 375) and high (more than 375).

The researchers found high levels of mutant p53 protein in tissue from 105 of the cancer patients. Women with p53-positive tumors, they found, were 7.7 times more likely to have a high number of LOCs than were women with p53-negative tumors, and 9.1 times more likely to have high LOCs than were the cancer-free controls. The findings suggest that women who ovulate frequently and who may be at risk for p53-positive tumors "can protect themselves by suppressing their ovulation," says co-author Joellen Schildkraut. She and Berchuck speculate that ovulation--which causes cells in the ovary to divide--is likely to spontaneously damage DNA, including the p53 gene, in ovarian cells. Indeed, p53-negative tumors did not appear to be linked to ovulation frequency. "This is one of the first studies to show that ovarian cancer is really a collection of a number of different cancers," adds Berchuck.

Experts are impressed with the study. The "provocative findings," write Stanford medical researchers Alice Whittemore and Valerie McGuire in an editorial accompanying the report, "provide a welcome advance in our understanding of the etiology of epithelial ovarian cancers." But the Stanford duo points out that testing for actual p53 mutations, rather than the more indirect overexpression of the gene, "would have provided a more compelling finding." The Duke researchers also say further research is needed in older patients, as the mean age of ovarian cancer onset is 60.

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