Inherited Mutations in RAD51D Gene Confer Susceptibility to Ovarian Cancer

Cancer Research UK-funded scientists have discovered that women who carry a faulty copy of a gene called RAD51D have almost a 1-in-11 chance of developing ovarian cancer. The finding that inherited mutations in the RAD51D gene confer susceptibility to ovarian cancer was reported in a study published online in Nature Genetics on August 7, 2011.

Cancer Research UK-funded scientists have discovered that women who carry a faulty copy of the RAD51D gene have nearly a 1-in-11 chance of developing ovarian cancer. The finding that inherited mutations in the RAD51D gene confer susceptibility to ovarian cancer was reported in a study published online in Nature Genetics on August 7, 2011.

(Photo: Cancer Research UK)

Although hereditary faults in RAD51D are thought to account for less than one in every hundred ovarian cancer cases – fewer than 60 women every year in the UK – this discovery could prove very important in the future in connection with the prevention and treatment of the disease in women who carry the faulty gene.

The team at The Institute of Cancer Research (ICR) examined DNA from women from 911 families with ovarian and breast cancer and compared differences in DNA with a control group of 1,060 people from the general population.

The team discovered eight germline (inherited) gene faults in the RAD51D gene in women with cancer, compared with one in the control group.

Ovarian cancer is the fifth most common cancer in women with approximately 6,500 cases diagnosed annually in the UK. The researchers estimate that RAD51D gene faults are present in almost one percent of women with ovarian cancer; that is, around 50 UK women each year.

Around one woman in 70 in the general population is at risk of developing ovarian cancer, but for those with a RAD51D gene fault this risk is increased to 1-in-11 – making these women six times more likely to develop the disease. The RAD51D gene fault also caused a slight increase in the risk of breast cancer.

The RAD51D gene is important for repairing damaged DNA. When the RAD51D gene is faulty, a key DNA repair pathway known as “homologous recombination” (HR) fails. This means DNA damage is not fixed and DNA faults build up in cells which make them more likely to turn into cancer.

The UK team also showed that cells with faulty RAD51D can be selectively destroyed by a relatively new class of cancer drugs called “PARP (poly (ADP-ribose) polymerase) inhibitors.” When the researchers tested the drugs on cells with the faulty RAD51D gene, they observed a dramatic effect – nearly 90 percent of the cells died, compared with just 10 percent of cells with fully functional RAD51D. These drugs are showing great promise in clinical trials for the treatment of breast and ovarian cancers with faults in the BRCA1 and BRCA2 genes, which are also important for repairing damaged DNA.

Professor Nazneen Rahman

Cancer Research UK-funded scientist and study author Professor Nazneen Rahman, head of the Division of Genetics and Epidemiology at The Institute of Cancer Research and The Royal Marsden cancer center, said:

“Women with a fault in the RAD51D gene have a 1-in-11 chance of developing ovarian cancer. At this level of risk, women may wish to consider having their ovaries removed after having children, to prevent ovarian cancer from occurring. There is also real hope on the horizon that drugs specifically targeted to the gene will be available.”

Professor Nic Jones

Professor Nic Jones, Cancer Research UK’s chief scientist, said:

“It’s incredibly exciting to discover this high risk gene for ovarian cancer. It’s 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. We believe the results of this research will help inform personalized treatment approaches and give doctors better information about risks of cancer to tell patients.”

Harpal S. Kumar, CEO, Cancer Research UK

Harpal Kumar, Cancer Research UK’s chief executive, said:

“Survival from ovarian cancer has almost doubled in the last 30 years. This landmark discovery is another piece of the jigsaw deepening our understanding of the disease. We hope this will have a significant impact in providing more personalised treatments for patients based on their genetic make-up, saving more lives from ovarian cancer. All of our research is generously funded by the public. This support has allowed us to invest heavily in the identification of DNA changes which paint a picture of which parts of a person’s gene set are linked to cancer. This life-changing discovery exemplifies the importance of this research and the importance of ongoing public support.”

Again, it is important to stress that faults in the RAD51D gene are rare, probably causing fewer than one in every 100 ovarian cancers. Yet for the small proportion of women who carry a faulty RAD51D gene, there is a chance of developing ovarian cancer, thereby making it a significant new finding.

Cancer Research UK is the largest single funder of ovarian cancer research in the UK – last year it spent more than £12 million of public donations on tackling the disease.

The RAD51D gene mutation study findings in relation to ovarian cancer susceptibility add to past evidence which links the gene to the disease. On April 21, 2010, Libby’s H*O*P*E*™ reported that a team of German researchers determined that RAD51C also increases a woman’s risk of breast and ovarian cancer.  Specifically, the identified risk for breast cancer in women with the RAD51C mutation was reported to be 60 percent to 80 percent, while the identified risk for ovarian cancer was 20 percent to 40 percent.

On November 11, 2010, we also reported that a separate group of U.K. researchers concluded that (i) HR-deficient status can be determined in primary ovarian cancer through a “RAD51 assay,” and (ii) such status correlates with in vitro response to PARP inhibition. Accordingly, the researchers concluded that potentially 50 percent to 60 percent of ovarian cancers patients could benefit from PARP inhibitors, but they noted that use of the RAD51 assay as a biomarker requires additional clinical trial testing. Although the RAD51 assay test that was used by these U.K. researchers to examine tumor samples in the laboratory is not yet suitable for routine clinical practice, the U.K. research team hopes to refine it for use in patients.

Sources:

• Loveday C et al., Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nature Genetics, August 2011, Published online 07 August 2011, doi:10.1038/ng.893.

• Landmark ovarian cancer discovery as scientists unveil high risk gene, Press Release, Cancer Research UK, August 7, 2011.

• New ovarian cancer gene is a significant step forward, Science Update Blog, Cancer Research UK, August 7, 2011.

About Cancer Research UK

• Cancer Research UK is the world’s leading cancer charity dedicated to saving lives through research.
• The charity’s groundbreaking work into the prevention, diagnosis and treatment of cancer has helped save millions of lives. This work is funded entirely by the public.
• Cancer Research UK has been at the heart of the progress that has already seen survival rates double in the last forty years.
• Cancer Research UK supports research into all aspects of cancer through the work of over 4,000 scientists, doctors and nurses.
• Together with its partners and supporters, Cancer Research UK’s vision is to beat cancer.

For further information about Cancer Research UK’s work or to find out how to support the charity, please call 020-7121-6699 or visit www.cancerresearchuk.org

About The Institute of Cancer Research (ICR)

• The ICR is Europe’s leading cancer research center.
• The ICR has been ranked the UK’s top academic research center, based on the results of the Higher Education Funding Council’s Research Assessment Exercise.
• The ICR works closely with partner The Royal Marsden NHS Foundation Trust to ensure patients immediately benefit from new research. Together the two organisations form the largest comprehensive cancer centre in Europe.
• The ICR has charitable status and relies on voluntary income.
• As a college of the University of London, the ICR also provides postgraduate higher education of international distinction.

Over its 100-year history, the ICR’s achievements include identifying the potential link between smoking and lung cancer which was subsequently confirmed, discovering that DNA damage is the basic cause of cancer and isolating more cancer-related genes than any other organization in the world.

For more information visit www.icr.ac.uk

About The Royal Marsden

• The Royal Marsden is a world-leading cancer centre specializing in cancer diagnosis, treatment, research and education.
• The Royal Marsden is also partners with The Institute of Cancer Research. Through this partnership, it undertakes groundbreaking research into new cancer drug therapies and treatments. The partnership makes The Royal Marsden the biggest and most comprehensive cancer center in Europe, with a combined staff of 3,500.