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.

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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.

Researchers Identify A New Breast & Ovarian Cancer Susceptibility Gene

German researchers identify a new breast and ovarian cancer susceptibility gene known as “RAD51C.”  The risk for breast cancer in women with the RAD51C mutation is 60 to 80 percent, while the risk for ovarian cancer is 20 to 40 percent.

The discovery 15 years ago that the genes BRCA1 and BRCA2 confer high risks for breast and ovarian cancer was a breakthrough for cancer prediction and therapy, especially for familial cases.  Now the research group of Prof. Alfons Meindl (Klinikum rechts der Isar of the Technische Universitaet Muenchen), in collaboration with other groups from Germany, the U.K., and the U.S., can identify another gene that increases susceptibility to breast and ovarian cancer. Their results have been published online in Nature Genetics. The identification of such high risk-conferring genes is a prerequisite for offering women tailored early recognition programs and more individualized therapies.

The gene newly identified as causing breast and ovarian cancer in familial cases is designated RAD51C. It is, like BRCA1 and BRCA2, essential for DNA repair within cells. Mutations in the gene can therefore cause either breast or ovarian cancer. In index cases from 1,100 German families with gynecological malignancies, six mutations within the RAD51C gene were found exclusively in 480 pedigrees [i.e., family trees] with occurrence of breast and ovarian cancer. The six RAD51C mutations were not found in 620 pedigrees with breast cancer only, or in 2,912 healthy German controls.  The risk for breast cancer in women with mutation of RAD51C is 60 to 80 percent, while the risk for ovarian cancer is 20 to 40 percent. As the cancers in such families were diagnosed significantly earlier than in women who developed sporadic breast or ovarian cancer, experts might also call the newly identified gene BRCA3.

“These results reinforce our assumption that various rare gene mutations contribute to hereditary breast and ovarian cancer. The now known genes that predispose women to breast and/or ovarian cancer only explain 60 percent of the high-risk families,” says TUM Professor Alfons Meindl, Klinikum rechts der Isar, but novel technologies allow the rapid identification of other such rarely mutated disease-causing genes.

“We are also optimistic that in the future the individual breast cancer risks for the majority of women can be determined. These risk predictions will allow the offering of tailored prevention and small meshed early recognition programs. Risk-aligned prevention will become a new clinical area,” explains Prof. Dr. Rita Schmutzler of the University Hospital of Cologne, one of the other main authors of the article.

About Technische Universitaet Muenchen

Technische Universitaet Muenchen (TUM) is one of Germany’s leading universities. It has roughly 420 professors, 7,500 academic and non-academic staff (including those at the university hospital “Rechts der Isar”), and 24,000 students. It focuses on the engineering sciences, natural sciences, life sciences, medicine, and economic sciences. After winning numerous awards, it was selected as an “Elite University” in 2006 by the Science Council (Wissenschaftsrat) and the German Research Foundation (DFG). The university’s global network includes an outpost in Singapore. TUM is dedicated to the ideal of a top-level research based entrepreneurial university. http://www.tum.de

About Klinikum rechts der Isar, Munich, Germany

The Klinikum rechts der Isar (on the right hand side of the river Isar) serves its patients with a highly skilled team of dedicated doctors, nurses, research scientists, and technical assistants. The Klinikum rechts der Isar is a university hospital of the Technische Universitaet Muenchen.  With a workforce of over 4,000 personnel, the university hospital is a renowned center for the care of the sick, for medical research, and for the teaching of medicine. The Klinikum rechts der Isar is composed of more than 30 separate clinics and departments treating some 45,000 in-house patients and 170,000 out-patients yearly. With more than 1,000 beds, the hospital covers the entire spectrum of modern medicine with state-of-the-art efficiency. Through the close cooperation between health care and research, the latest advances in medical techniques can be quickly integrated into patient treatment procedures.

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Beyond BRCA1 & BRCA2: U.K. Researchers Identify Genetic Defect That Could Increase Risk of Ovarian Cancer Up To 40%

Scientists have located a region of DNA which – when altered – can increase the risk of ovarian cancer according to research published in Nature Genetics today. An international research group led by scientists based at the Cancer Research UK Genetic Epidemiology Unit, at the University of Cambridge and UCL (University College London) searched through the genomes of 1,810 women with ovarian cancer and 2,535 women without the disease from across the UK. …The scientists estimate that there is a 40 per cent increase in lifetime risk for women carrying the DNA variation on both copies of chromosome nine compared with someone who doesn’t carry it on either chromosome. The risk for women carrying the variation on both chromosomes is 14 in 1000 – compared with [10] ten in 1000 [in the general population]. … The lifetime risk for a woman carrying the DNA variant on one copy of the chromosome is increased by 20 per cent from ten in 1000 to 12 in 1000. …

Genetic link to ovarian cancer found

Cancer Research UK

SUNDAY 2 AUGUST 2009

Cancer Research UK Press Release

Scientists have located a region of DNA which – when altered – can increase the risk of ovarian cancer according to research published in Nature Genetics today.

An international research group led by scientists based at the Cancer Research UK Genetic Epidemiology Unit, at the University of Cambridge and UCL (University College London) searched through the genomes of 1,810 women with ovarian cancer and 2,535 women without the disease from across the UK. They analysed 2.5 million variations in DNA base pairs – the letters which spell out the genetic code – to identify common spelling ‘errors’ linked to ovarian cancer risk.

The scientists identified the genetic ‘letters’- called single nucleotide polymorphisms (SNPs) – which when spelled slightly differently increase ovarian cancer risk in some women. This is the first time scientists have found a SNP linked uniquely to risk of ovarian cancer and is the result of eight years of investigations. With the help of the international Ovarian Cancer Association Consortium (OCAC), they then looked at more than 7,000 additional women with ovarian cancer and 10,000 women without disease from around the world to confirm this finding.

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The region of risk DNA is located on chromosome nine – there are 23 pairs of each chromosome in humans, one of each pair inherited from each parent. The scientists estimate that there is a 40 per cent increase in lifetime risk for women carrying the DNA variation on both copies of chromosome nine compared with someone who doesn’t carry it on either chromosome. The risk for women carrying the variation on both chromosomes is 14 in 1000 – compared with [10] ten in 1000 [in the general population].

Approximately 15 per cent of women in the UK population carry two copies of the variant DNA.

The lifetime risk for a woman carrying the DNA variant on one copy of the chromosome is increased by 20 per cent from ten in 1000 to 12 in 1000. Approximately 40 per cent of women in the UK carry one copy.

Senior author Dr. Simon Gayther, whose work is supported by Cancer Research UK and The Eve Appeal charity which fundraises for the gynaecological cancer research team based at UCL, said: “The human DNA blueprint contains more than 10 million genetic variants. These are part and parcel of our characteristics and make-up – but a handful will also increase the chances of some women getting ovarian cancer and we have found the first one of these.”

“There is now a genuine hope that as we find more, we can start to identify the women at greatest risk and this could help doctors to diagnose the disease earlier when treatment has a better chance of being successful.”

Dr. Andrew Berchuck, head of the international Ovarian Cancer Association Consortium steering committee, said: “This study confirms that ovarian cancer risk is partly determined by genetic variants present in a large number of women. This initial discovery and others that will likely follow in the future lay the groundwork for individualised early detection and prevention approaches to reduce deaths from ovarian cancer.”

Ovarian cancer is the fifth most common cancer in women in the UK with around 6,800 new cases diagnosed each year in the UK – 130 women every week. It is the fourth most common cause of cancer death in women in the UK with around 4,300 deaths from the disease in the UK each year.

BRCA1 and BRCA2 are high risk genes which cause breast cancer and are already known to significantly increase the risk of ovarian cancer- but faults in these genes are rare and probably cause less than five per cent of all cases of ovarian cancer.

Lead author, Professor Dr Paul Pharoah, a Cancer Research UK senior research fellow at the University of Cambridge, said: “We already know that people with mistakes in the BRCA1 and BRAC2 genes have a greater risk of ovarian cancer – but on their own they don’t account for all of the inherited risk of the disease. “It is likely that the remaining risk is due to a combination of several unidentified genes – which individually carry a low to moderate risk. Now we have ticked one off, the hunt is on to find the rest.”

Rose Lammy, the mother of David Lammy MP [Member of Parliament] for Tottenham and Minister for Higher Education and Intellectual Property, died of ovarian cancer in 2008. Rose Lammy’s DNA sample was included in the study, and she carried both risk alleles of the new genetic marker that researchers have identified.

David Lammy said: “I am pleased that Mum’s sample was included in this study as it is one step towards earlier diagnosis of ovarian cancer when treatment is more successful. We now know the fact that she had this altered DNA meant that her lifetime risk had risen from 10 in 1,000 to 14 in 1,000, an increase of 40 per cent compared to those women who don’t carry this DNA variation. Dr Lesley Walker, director of cancer information at Cancer Research UK, added: “This is an important discovery. Our researchers have worked as part of a huge collaboration to establish the regions of DNA that can increase someone’s risk of developing ovarian cancer. “This research paves the way for scientists to discover even more genes linked to ovarian cancer and could lead to new approaches to treat or prevent the disease – crucially it will help doctors manage women who are at increased risk.”

Source: Genetic link to ovarian cancer found, Cancer Research U.K. Press Release & Video, 02 Aug. 09.

Reference: Honglin Song et al. (2009). A genome-wide association study identifies a new ovarian cancer susceptibility locus on 9p22.2 Nature Genetics 10.1038/ng.424.