Today, Cancer Research UK-funded scientists led by Professor Nazneen Rahman at The Institute of Cancer Research announced a major step forward in our understanding of the genetic faults that underpin some cases of ovarian cancer.
Publishing their results in the prestigious journal Nature Genetics, the team revealed that women who inherit a faulty version of the RAD51D gene have a one in 11 chance of developing ovarian cancer, compared with one in 70 for the general population.
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 for helping to prevent or treat the disease in women who carry the faulty gene.
Let’s take a closer look at what the scientists did, and what it means for our understanding of ovarian cancer.
Inherited gene faults and ovarian cancer
More than one in 10 ovarian cancers are thought to be due to an inherited gene fault. This is particularly true in families affected by many cases of the disease.
Back in the 1990s, Cancer Research UK-funded scientists played a vital role in the discovery of BRCA1 and BRCA2. Having a faulty version of either of these genes significantly increases the chance of developing breast and ovarian cancer – a discovery that has led to genetic testing, prevention advice and now targeted cancer treatment for affected women.
Carrying a faulty version of BRCA1 means a woman has about a five in ten chance of developing ovarian cancer, while a faulty version of BRCA2 leads to a roughly two in ten chance of developing the disease – a far higher risk than the general population.
In addition, Cancer Research UK-funded scientists recently identified a number of genetic variations that increase the risk of ovarian cancer by a relatively small amount, but are more common in the population than BRCA faults.
Adding together all of this information, researchers still can’t account for all the cases of ovarian cancer that are likely to be due to gene faults. So there must be other genes out there. And thanks to the work of Professor Rahman and her team, we now know the identity of one of them.
Starting the search
Hunting for cancer genes is a tricky business. The human genome contains roughly 25,000 genes, made up of around 3 billion DNA ‘letters’, so searching for specific gene faults in this volume of genetic information is like looking for individual spelling mistakes in a whole library.
To make their search a bit easier, the scientists focused on genes that are important in repairing DNA faults – the root cause of cancer – so faults in this process understandably increase the chances of developing the disease. Both BRCA1 and BRCA2 are important for repairing DNA damage, explaining why faults in either gene lead to an increased cancer risk.
One of the team’s prime suspects was a gene called RAD51D, which is involved in repairing DNA damage. To find out if it was involved in ovarian cancer, Professor Rahman and her colleagues looked closely at the RAD51D gene in people from more than 900 families affected by hereditary breast and ovarian cancer, who didn’t have faults in BRCA1 or BRCA2.
The researchers noticed eight different mistakes in RAD51D in people from the affected families – mainly families affected by several cases of ovarian cancer. In contrast, a fault in RAD51D turned up in just one out of more than 1,000 people from families unaffected by hereditary cancer.
Further tests and computer analysis showed that a woman carrying a fault in RAD51D is more than six times more likely to develop ovarian cancer than someone without. But even though they looked at families affected by both ovarian and breast cancers, when the team analysed their data in detail, they discovered that RAD51D faults weren’t significantly linked to an increased risk of breast cancer (or if there is a link, then it’s very small).
Potential for PARP inhibitors
We’ve written a lot in the past about PARP inhibitors – drugs originally designed to treat breast, ovarian and prostate cancers carrying faulty BRCA genes. Recent research has shown that these drugs may have a much wider use, by targeting other gene faults.
As a final experiment, Professor Rahman’s colleague Professor Alan Ashworth investigated whether PARP inhibitors might also be effective against ovarian cancers with RAD51D faults. When they tested the drugs on cells lacking RAD51D, the scientists saw a dramatic effect – nearly 90 per cent of the cells died, compared with just ten per cent of cells with fully functional RAD51D.
This striking result suggests that PARP inhibitors could be an effective treatment for women with ovarian cancer linked to faulty RAD51D, although this needs to be tested in clinical trials.
What does this mean for women?
This discovery is fresh out of the lab, so it’s likely that the benefits of this research will take a while to filter through to clinical use.
However, it might be possible to be able to offer families with ovarian cancer a genetic test to see if the RAD51D gene is involved within a few years. This may help us to offer women carrying a faulty version personalised treatments such as a PARP inhibitor. This is exactly the kind of tailored treatment we’ve been talking about recently on the blog – for example, through our Stratified Medicine Programme.
Testing for RAD51D faults could also have important implications for early detection and prevention of ovarian cancer. Professor Rahman suggests that female family members carrying a faulty version of RAD51D could be offered the opportunity to have their ovaries removed by keyhole surgery aged around 50. This would drastically reduce the chance of developing ovarian cancer.
Finally, it’s 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 gene, the chance of developing this type of cancer is high, making it a significant new finding.
Into the future
The discovery that faults in RAD51D are implicated in ovarian cancer is yet another piece in the complex puzzle linking our genetic makeup and lifestyle to our risk of cancer. As we know from this research, and from studies on other genes, carrying a particular gene fault isn’t a 100 per cent guarantee that a person will develop cancer. Lifestyle factors, hormones and chance also play a role.
Cancer Research UK is investing millions of pounds every year in research aimed at unravelling the genetic complexities that underpin cancer – the International Cancer Genome Consortium is just one example of the work we’re doing in this area.
In the future, this will lead to more personalised treatment for all people with cancer, and better information about individual risk.
Loveday et al, Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nature Genetics, August 2011
Recent estimates using a new calculation method suggest that the lifetime risk for ovarian cancer in the general population has shifted from 1 in 70 to 1 in 54. However, because the researchers have used 1 in 70 as the basis for their calculations, this is the figure we have used throughout our press materials so we can directly compare the lifetime risk of those with the faulty gene with the general population.
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