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14-08-2011 | Gynaecology | Article

RAD51D mutations may increase ovarian cancer risk


Free abstract

MedWire News: Women with mutations in the RAD51D gene may be predisposed to developing ovarian cancer, UK study data show.

Nazneen Rahman (Institute of Cancer Research, Sutton) and colleagues explain that the RAD51 is a DNA recombinase that plays a central role in DNA repair by homologous recombination.

Recently, mutations in the gene encoding one of five RAD51 paralogs (RAD51C) were identified in families with breast and ovarian cancer.

In the present study, Rahman and team investigated whether mutations in a second RAD51 paralog, RAD51D, are also involved in cancer susceptibility.

They sequenced the RAD51D gene in samples from 911 unrelated individuals from families with a history of breast and/or ovarian cancer, and compared their findings with those from 1060 population-based controls.

The team identified eight inactivating RAD51D mutations among the breast-ovarian cancer families, compared with just one mutation among the controls.

The mutations were not equally distributed within the series, and were primarily observed in families with more than one case of ovarian cancer. Indeed, four of the mutations were detected in the 235 families with two or more cases of ovarian cancer, and three were detected in the 59 families with three or more cases of ovarian cancer.

Rahman et al calculated that RAD51D mutation carriers had a significant 6.3-fold increased risk for ovarian cancer, but no increased risk for breast cancer, compared with noncarriers.

Further investigation showed that cells deficient in RAD51D are sensitive to treatment with a poly (ADP-ribose) polymerase inhibitor, "suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carrier," the researchers remark.

They estimate that approximately 0.6% of unselected individuals with ovarian cancer will harbor RAD51D mutations, adding that these individuals will soon be readily identifiable with the introduction of routine genetic testing.

"Their identification will also be of potential value to female relatives, as those relatives with mutations will be, on average, at an approximately six-fold increased risk for ovarian cancer, which equates to an approximate 10% cumulative risk by age 80," write the researchers in the journal Nature Medicine.

An appreciable proportion of women at this level of risk may consider prevention strategies such as laparoscopic oophorectomy, which is well tolerated and is already undertaken in many women with BRCA mutations, they add.

Rahman and co-authors conclude that their data "clearly show that RAD51D is an ovarian cancer predisposition gene, but further studies in familial and sporadic ovarian cancer series would be of value to further clarify the risks of ovarian cancer."

By Laura Dean

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