BRCA genes and ovarian cancer

Canadian cancer researchers recently reported that around 18 per cent of women with primary serous epithelial ovarian cancer have germline mutations in the tumour-suppressor genes BRCA1 and BRCA2, better known for their role in breast cancer.

Professor David Bowtell, a lead researcher in one of the world's largest studies of ovarian cancer, says the Canadian study was significant because of its unprecedented size - 1000 cases - and its finding that BRCA germline mutations are more common that previously believed in invasive ovarian cancer, including in women with little family history of the disease.

The Peter McCallum Cancer Institute researcher said that, as a rule of thumb, any woman with a 10 per cent or greater chance of carrying a specific germline mutation is offered genetic testing.

If new studies validate the Canadian data, it would substantially change the guidelines for genetic testing of women for susceptibility to ovarian cancer.

"The implications of the work are two-fold," Bowtell says. "First, identifying genetic risk can have important implications for family members. Second, there are new drugs such as PARP inhibitors that specifically target tumours with a mutation in BRCA genes."

The BRCA1 and BRCA2 genes are members of the large class of tumor-suppressor genes that detect mutations during cell replication and activate DNA-repair mechanisms, or trigger apoptosis.

Dr Gillian Mitchell, director of Peter Mac's Familial Cancer Centre, is a lead clinician-researcher on an international clinical trial of inhibitors of the PARP DNA-repair enzyme.

Bowtell says the therapy is based on the idea that if an ovarian tumour is defective for BRCA-initiated DNA repair, that it will be reliant on PARP for single-stranded DNA-break repairs, and therefore sensitive to PARP inhibitors.

Ovarian cancer is less common than breast cancer - a woman's lifetime risk of developing ovarian cancer is about 1/70 to 1/100. But it has a lower survival rate because it is usually diagnosed late, when tumours are at stage 3 or 4, and less responsive to treatment. Median survival time after diagnosis is around 34 months.

Bowtell says the large cohort of Australian women recruited to the Australian Ovarian Cancer Study (AOCS) is ideal for validating the Canadian findings.

When it began in 2001, AOCS sought to recruit 1000 volunteers, but by 2006 had 2456 subjects, from every Australian state.

Bowtell and Mitchell have recently received a translational research award from the US Department of Defense's ovarian cancer research program, one of only five awarded in 2007, to begin testing the AOCS cohort, which has 1200 patients with invasive cancers who are eligible to participate.

Researchers are collecting detailed epidemiological data, looking for clues to the way known environmental risk factors interact with predisposing genetic factors to cause ovarian cancer. The findings could suggest prevention strategies.

They are also performing detailed genomic analyses of cancerous tissue samples from each subject, recording regions of chromosomal DNA gain, duplication and loss, patterns of gene expression, and biochemical changes in response to treatment.

The data will allow oncologists to assess how individual patients are likely to respond to different therapies, and the effect on patient survival.

As members of the international Ovarian Cancer Association Consortium (OCAC), AOCS researchers are helping to find variants of other genes that may contribute to the development of ovarian cancer.

Bowtell and his Peter Mac colleagues are focusing on identifying somatic-cell mutations that drive the development and growth of ovarian tumours.

"We plan to begin large-scale sequencing of cancer genes soon, and map the mutations back onto different tumour sub-types," Bowtell says.

New findings will be fed forward to the clinic to help develop more targeted treatments that may improve survival times.

"We'd like to know whether carriers of BRCA mutations do better than non-carriers - the data are not particularly comprehensive.

"BRCA genes are very important in ovarian cancer and we would like to understand the molecular changes in tumours arising in germline carriers, and their relationship to those with somatic mutations and silencing by methylation.

"We're also very interested in exploring the molecular changes that occur between primary treatment and the emergence of progressive disease, especially what type of tumours remain chemosensitive, and which develop resistance."