BioWorld Today Correspondent

LONDON – A new gene with an important role in ovarian cancer has been identified. Women with the mutant gene have a 10 percent lifetime risk of developing the disease.

The gene, RAD51D, plays an important role in DNA repair. Initial results suggested cells with a mutant copy of the gene, so that the protein it encodes loses its function, are sensitive to the class of drugs known as PARP inhibitors.

Nazneen Rahman, head of the division of genetics and epidemiology at the Institute of Cancer Research and the Royal Marsden Hospital in London, told BioWorld Today that the finding "demonstrates that there are genes with significant impact that can be identified.

"We have only looked at a relatively small number of genes, but this study suggests strongly that there are going to be a number of these and that, in time, we will increasingly be able to offer personalized management for patients, based on their genetic profile," she said.

Rahman and her colleagues reported their findings in the Aug. 7, 2011, issue of Nature Genetics, in a paper titled: "Germline mutations in RAD51D confer susceptibility to ovarian cancer." In their conclusion, they wrote, "We estimate that only 0.6 percent of unselected individuals with ovarian cancer will harbor RAD51D mutations, but as we enter an era in which genetic testing will become routine, such individuals will be readily identifiable."

The finding also will be clinically useful when advising relatives of those found to have the mutation, Rahman said.

"For those with this mutation, the lifetime risk of developing ovarian cancer is 10 percent. At that level, quite a lot of women, particularly if they have had relatives with ovarian cancer, would consider having prophylactic oophorectomy once they have completed their families. This strategy is already utilized widely among those who have mutations in either BRCA1 or BRCA2," she said.

Following recent discoveries linking genes that operate within the DNA repair pathway to both breast and ovarian cancers, Rahman and her team decided to investigate RAD51D.

They sequenced the gene in 911 individuals from families with members affected by breast and ovarian cancers, and in 1,060 people from the general population.

They found eight mutations – all resulting in loss of function in the protein encoded – in the cancer families, and only one in the general population.

Rahman noted that RAD51D is in the same DNA repair pathway as BRCA1 and BRCA2. "Both genes are part of the homologous recombination pathway, which repairs double-stranded DNA breaks," she said. "As the drugs known as PARP inhibitors have shown great promise in individuals with BRCA mutations, and RAD51D is in the same pathway, it seemed reasonable to hypothesize that [cells with mutations in this gene] might also be sensitive to PARP inhibitors."

To test that hypothesis, researchers used short interfering RNA to silence the RAD51D gene in cells and then added PARP inhibitor olaparib (AstraZeneca plc). "We were able to show," Rahman said, "that these cells were indeed sensitive to PARP inhibitors, at the same level as cells with BRCA mutations. Although this is work in cells, it would be reasonable [to assume] that, within a relatively short space of time, if you were a RAD51D mutation carrier, you could also be eligible for the [ongoing] PARP trials."

In addition, as platinum-based drugs have been shown to be particularly effective in BRCA mutation carriers, the same likely is to be true in RAD51D mutation carriers, she added.

Nic Jones, chief scientist at Cancer Research UK, which funded the study, said: "It's incredibly exciting to discover this high-risk gene for ovarian cancer. It is further evidence that a range of different high-risk genes are causing the development of breast and ovarian cancer, and we hope there are more waiting to be discovered in different cancers."

Future work for Rahman and her team will focus on using next-generation sequencing technology to carry out much wider gene analysis. "Over the past few years, we have been restricted to looking at relatively small numbers of genes," she said. "But we're currently engaged in doing an experiment where we are looking at all the DNA repair genes – more than 400 of them – and looking at all the protein-coding genes in our sample series . . . in order to identify the genetic causes of cancer, looking at both breast and ovarian cancer."