A single genetic fault “increases a woman’s risk of ovarian cancer six-fold”, The Independent has today reported.
The estimate is based on new research looking at the prevalence of a mutation in the RAD51D gene, which is normally involved in the repair of damaged DNA. To test its role in ovarian cancer scientists examined the gene in people from 911 families affected with breast and ovarian cancer. Just under 1% of these families were found to carry a mutation in this gene, compared with just under 0.1% of healthy individuals.
Although women who carry mutations in RAD51D are estimated to be at about six times the risk of ovarian cancer than those who do not, this must be considered in context. The mutation itself is rare (estimated to be found in 0.1% of women), and carrying it does not guarantee that a woman will develop the disease. It’s also thought that over 99% of women with ovarian cancer do not carry mutations in this gene.
This kind of study gives researchers and doctors greater insight into diseases such as ovarian cancer, and may help identify the people at greatest risk while tailoring treatments to give the greatest benefit.
Where did the story come from?
The study was carried out by researchers from the Institute of Cancer Research and other research centres and genetics services in the UK. The study was funded by Cancer Research UK, the US Department of Defense, Breakthrough Breast Cancer and the Institute of Cancer Research in the UK.
The study was published in the peer-reviewed scientific journal Nature Genetics.
The Independent, Daily Mirror and Daily Express covered this story. The Independent provides helpful figures to put the level of risk in carriers in context. For example, it states that about 6,500 women are diagnosed with ovarian cancer each year, of whom about 40 or 50 might carry a mutation in the RAD51D gene.
The Express and Mirror focused on the possibility of using information from this study to test for ovarian cancer. It is important to view such a possibility in context: the mutations examined in this research are rare, even in women with ovarian cancer, and were more common in women from families with higher numbers of ovarian cancer cases. This suggests that if genetic testing for these specific mutations in this gene was to be carried out, it would be targeted at women with a strong family history of ovarian cancer rather than used as a mass screening tool.
What kind of research was this?
This was a case control study that looked at whether mutations in a gene called RAD51D are associated with ovarian and breast cancer. The researchers wanted to look at this gene because in 2010 another group of researchers identified mutations in a related gene (RAD51C) in people who came from families affected by breast and ovarian cancer, but not in healthy individuals. Both of these genes (RAD51C and RAD51D) contain the blueprints for proteins involved in repairing damaged DNA. Some genes affect the risk of both breast and ovarian cancer, such as the BRCA1 and BRCA2 genes. This study aimed to determine whether mutations in the RAD51D gene were also responsible for the increased risk in families affected by both these types of cancer.
In this type of study, researchers compare the genetic make-up of people with the disease (cases) with that of people without the disease (controls). If variations in a particular gene are more common in cases, then the mutation may be contributing to people’s risk of developing the disease. This type of study is appropriate for answering this type of question.
What did the research involve?
The researchers looked at the sequence of “letters” that make up the DNA in the RAD51D gene in 911 people from families affected by breast and ovarian cancer, and in 1,060 controls whose families were not affected. To be eligible for inclusion the affected families had to have at least one case of breast cancer and at least one case of ovarian cancer. Families also had to be free from mutations in the BRCA1 and BRCA2 genes, which are known to contribute to the risk of both breast and ovarian cancer.
The researchers assessed whether the patients (cases) carried any mutations that were less common or not present at all in the controls. Once they identified such mutations, they tested for them in the patients’ relatives, as well as 737 people from families affected by breast cancer but not ovarian cancer. They also estimated the effect that mutations had on the risk of ovarian and breast cancer using the data they had from the cases and controls.
Finally, they carried out an experiment to look at whether “switching off” the RAD51D gene in tumour cells in the laboratory made them more sensitive to an experimental drug called olaparib, which is currently being tested as a treatment for various types of cancer. It is a member of a family of drugs called PARP inhibitors, which block the actions of an enzyme that normally allows cells to repair DNA. These drugs are not currently licensed for medical use outside of clinical trials. They are being investigated in trials using them to treat patients with mutations in BRCA1 or BRCA2, which are genes that normally help the body to repair DNA damage.
What were the basic results?
The researchers identified mutations that would stop RAD51D working in eight of the 911 people (0.9%) from families affected by breast and ovarian cancer. These types of mutations were only found in one of the 1,060 control participants (0.09%). There were no RAD51D mutations in 737 people from families affected by breast cancer but not ovarian cancer.
Mutations in RAD51D were more common in people from families with more than one case of ovarian cancer. There were four cases of RAD51D mutations in the 235 families (1.7%) with two or more cases of ovarian cancer, and three cases of RAD51D mutations in the 59 families (5.1%) with three or more cases of ovarian cancer.
The researchers then looked at 13 relatives of the affected individuals who were known to carry a RAD51D mutation. All five of the relatives who had breast or ovarian cancer carried the family mutation, but only two out of the eight relatives who did not have breast or ovarian cancer carried the family mutation.
The researchers estimated that carrying a RAD51D mutation increased a person’s risk of ovarian cancer by just over six-fold (relative risk [RR] 6.30, 95% confidence interval [CI] 2.86 to 13.85). They put this into context by saying that this would mean that a woman who carried a RAD51D mutation would have about a 10% risk of developing ovarian cancer by the time she reached the age of 80.
Carrying a RAD51D mutation did not appear to increase a person’s risk of breast cancer (RR 1.32, 95% CI 0.59 to 2.96; a difference in risk that is not statistically significant).
In their laboratory experiments, the researchers found that “switching off” the RAD51D gene made tumour cells more sensitive to the drug olaparib.
How did the researchers interpret the results?
The researchers concluded that testing for the RAD51D mutation may be useful in women with ovarian cancer and their families. They estimate that only about 0.6% of people with ovarian cancer from the general population will have mutations in RAD51D. They say that these people will be “readily identifiable” as genetic testing becomes “routine”, and that their experiments suggest that they may be suitable for treatment with PARP inhibitor drugs.
The researchers also commented that identifying female relatives who carry the mutation may be of value, as it might allow them to consider surgical removal of their ovaries – a choice made by many women with BRCA mutations, they added.
This study provides evidence of a role for RAD51D mutations in ovarian cancer in families affected by both ovarian and breast cancer. Further studies in people with sporadic ovarian cancer (where there is no family history of the disease), as well as other affected families, will allow researchers to confirm their results.
It is important to note that mutations in RAD51D are not common in the general population, with about 0.1% women (1 in 1,000) estimated to be carriers. Although women who carry mutations in RAD51D have an increased risk of ovarian cancer, not all carriers will develop the disease. Figures from Cancer Research UK suggest that carriers of a RAD51D mutation have a 1 in 11 chance of developing the disease, compared to a 1 in 70 risk in the general population.
It is also worth noting that only 0.6% of all women with ovarian cancer are estimated to carry mutations in RAD51D. Mutations in this study were more common in women from families with a history of ovarian cancer, suggesting that if genetic testing for these mutations were to be carried out, they are likely to be targeted to women with a strong family history of ovarian cancer.
Based on their results, the researchers suggest that PARP inhibitor drugs may be useful in women with ovarian cancer who have RAD51D mutations. Cancer Research UK reports that these drugs have already shown promise in the treatment of women with the types of ovarian or breast cancer associated with BRCA1 and BRCA2. However, PARP inhibitors are currently unlicensed, experimental drugs. Further clinical trials will be needed to examine their effectiveness in women with RAD51D mutations.
This kind of study gives researchers and doctors greater insight into ovarian cancer, and may help identify those at the greatest risk while tailoring treatments to give the greatest benefit.
View the article: Loveday C, Turnbull C, Ramsay E et al. Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nature Genetics, August 8 2011