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Memorial Sloan-Kettering Team Confirms Link Between BRCA2 Mutation and Prostate Cancer

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BRCA2 mutations appear to play a significant role in prostate cancer.

Men who inherit the genetic mutation are five times more likely to develop the cancer than non-carrying men, according to a new study conducted at Memorial Sloan-Kettering Cancer Center.

The risk, which researchers called “significantly elevated,” may encourage physicians to prescribe existing BRCA1/2 tests to some men.

“Men with a family history of close relatives with early-onset breast cancer or ovarian cancer … may actually want to consider genetic counseling and testing for BRCA mutations,” said Noah Kauff, a gynecologist and geneticist at Memorial Sloan-Kettering and a co-author of the study.

To be sure, pharmacogenomics researchers and oncologists have suspected that a link exists between BRCA1/2 mutations and prostate cancer. The Breast Cancer Linkage Consortium, a loose “cooperative” of scientists who “share a major interest in inherited breast and ovarian cancer,” have suggested that male carriers of BRCA1/2 mutations are at increased risk for prostate cancer, yet several prominent researchers have suggested in studies that the frequency of these mutations in certain men with the disease do not confirm these theories.

But the Memorial Sloan-Kettering findings are “the first study of its type to confirm the link,” Kenneth Offit, chief of the Clinical Genetics Service at the clinic, and senior author of the study, said in a statement last week.

Offit and his colleagues found that men who carry the BRCA2 mutation are between three and five times as likely as men without the mutation to develop prostate cancer.

To arrive at their results, the scientists obtained DNA from 251 Ashkenazi Jewish men diagnosed with the disease. The researchers stressed in their study that they did not choose these men on the basis of personal or family history.

The scientists tested the men for the presence of BRCA1/2 mutations and compared their findings to specimens taken from 1,472 healthy men. The team analyzed DNA from case samples for three common Ashkenazi Jewish founder mutations in BRCA1 and BRCA2. They purified DNA using the QiaAmp Blood DNA midi kit, made by Qiagen.

In their study, which appears in the May 1 Clinical Cancer Research, the researchers reported that 13 of the 251 cases, or 5 percent, carried either BRCA1 or BRCA2 mutations. Of these, four had BRCA1 185delG, one had BRCA1 5382insC, and eight had BRCA2 6174delT.

In the control group, 28 samples, or 1.9 percent, tested positive for either BRCA1 or BRCA2 mutations. Nine had BRCA1 185delG, three had BRCA1 5382insC, and 16 had a BRCA2 6174delT mutation, the scientists reported.

“When stratified by gene, the risk for prostate cancer was 4.8 times higher in carriers of a specific BRCA2 mutation than in the healthy individuals tested,” the scientists wrote in their study.

Kauff added that although the study focused on patients of Ashkenazi Jewish ancestry, “the results may apply to all individuals with BRCA2 mutations.”

The researchers also said men in the study who carried the mutation were roughly the same age when they developed their prostate cancer as “most men” with the disease in the general population — older than age 50.

“This would indicate that prostate cancer screening may begin at age 50, as is recommended in the general population, assuming the findings are confirmed in future studies,” Sherri Donat, a urologic surgeon at Memorial Sloan-Kettering and co-author of the study, said in the statement.

Men who may be at risk for carrying BRCA2 mutations — such as those who belong to a family in which women have been diagnosed with BRCA1/2-related breast or ovarian cancer —- “should avail themselves of prostate cancer screening,” Kauff told Pharmacogenomics Reporter.

“Men with a family history of close relatives with early-onset breast cancer or ovarian cancer — and these could be individuals of Ashkenazi heritage or not — may actually want top consider genetic counseling and testing for BRCA mutations,” he said.

Kauff said these men either would undergo BRCA1 or BRCA2 gene-sequencing tests that are currently performed on women suspected of being carriers, or would be given a test to confirm the presence of a specific genetic change common in Ashkenazi individuals if they are of Eastern European or Jewish descent.

Over the last decade, BRCA1/2 mutations have been implicated in breast and ovarian cancers. They have even been linked to colorectal cancer, though research, notably a study that appeared in the Jan. 7 Journal of the National Cancer Institute by Offit and Memorial Sloan-Kettering colleague Tomas Kirchhoff, has discounted this correlation.

Asked if pharmacogenomics researchers will continue to hunt other genes that may elevate the risk of malignancies, Kauff said: “We’re not there yet. Clearly, there are almost certainly other genetic modifiers, because the vast majority of men who have a BRCA2 mutation will not develop prostate cancer.

“Actually, looking at other genes that may modify BRCA2 or other as-yet unidentified genes, may actually help us predict who is at risk,” he said.

—KL

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