Defective DNA-repair gene increases risk of Ovarian Cancer

According to a study conducted at the Institute of Cancer Research (ICR), study lead Professor Nazneen Rahman demonstrated that compared to 1 in 70 women in the general population, 1 in 11 women with a defective copy of a DNA repair gene called RAD51D are at a risk of developing ovarian cancer. The study published in the 7 August online issue of Nature Genetics was funded by the landmark Cancer Research UK. Since a certain class of already developed drugs has been found to be effective in targeting affected cells, personalized treatment is expected to be available more rapidly.

This milestone study represents a remarkable breakthrough in determining how certain cases of ovarian cancer are caused by defective genes, and there is “real hope on the horizon that drugs specifically targeted to the gene will be available,” said Nazneen Rahman who is the Professor of Human Genetics and Section Chair of Cancer Genetics at ICR.
A defective gene results in the failure of an important repair pathway causing the cells to build-up damaged DNA thereby increasing their risk of turning cancerous. The damaged DNA can be repaired by RAD51D.

The study involved a DNA assessment of women from 911 families with ovarian and breast cancer in comparison with DNA of 1,060 people in the general population that made up the control group.

Compared with only one mutation in the control group, Rahman and her colleagues identified eight inactivating RAD51D mutations in non-familial women with cancer. Three mutations were identified from 59 families comprising three or more individuals with ovarian cancer, thus establishing the strongest association with ovarian cancer.
Treatment with a new class of cancer drug called a PARP inhibitor was found to sensitize the cells that were RAD51D deficient “suggesting a possible therapeutic approach for cancers arising in RAD51D mutation carriers,” noted the authors.

Poly ADP ribose polymerase (PARP) is an enzyme involved in several cell processes including DNA repair and programmed cell death, and a class of drugs that limits their action is known as PARP inhibitor.
Clinical trials for breast and ovarian cancers caused by BRCA1 and BRCA2 gene mutations are already seeing potential results due to treatment with PARP inhibitors. Similar to PARP, BRCA1 and BRCA2 are also genes involved in damaged DNA repair.

Nearly 6,500 women in the UK are annually diagnosed with ovarian cancer, which is fifth most prevalent cancer seen in women. It often progresses without any obvious symptoms, and regrettably, the chances of survival are much low on diagnosis since many women only discover the disease once it has spread to other parts of the body.
According to researchers, less than 1% of ovarian cancer women have RAD51D mutations, which affect nearly 50 individuals in the UK annually.

“Women with a fault in RAD51D gene have a one 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 occurring,” said Rahman.

Chief scientists at Cancer Research UK, Professor Nic Jones, stated that it was “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,” said Jones, adding that they believe “the results of this research will help inform personalized treatment approaches and give doctors better information about risks of cancer to tell patients.”

Chief executive of Cancer Research UK, Harpal Kumar, said: “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.”
Cancer Research UK is a charity, and the single largest funding association in the UK that spent more than £12 million of publicly donated funds on combating ovarian cancer last year.