Cancer and Your Genes

RAD51D - A New Hereditary Ovarian Cancer Gene With Important Implications

The last couple of decades have brought significant advances in our ability to estimate ovarian cancer risk and, in some cases, prevent it - largely due to the discovery of the impact of mutations in the BRCA1 and BRCA2 genes on risk.  However, progress for women with a significant family history of ovarian cancer in families where BRCA1/2 mutations have been ruled out has been painstakingly slow.

Recently, physicians and scientists discovered that mutations in a gene called RAD51C account for hereditary breast and ovarian cancer risk in a modest number of families with a compelling family history of these cancers, but no mutations in the BRCA1 and BRCA2 genes.

In a new study published online at Nature Genetics today, scientists led by Dr. Nazneen Rahman at The Institute of Cancer Research (Sutton, UK), have clearly shown that inherited mutations in another gene called RAD51D appear to be the cause of ovarian cancer risk in some families that do not have mutations in the BRCA1 or BRCA2 genes.

If you have a compelling family history of ovarian cancer that is not explained by a mutation in the BRCA1 or BRCA2 gene, a mutation in the RAD51D gene could be the explanation.

RAD51D is an Ovarian Cancer Susceptibility Gene

Years of study of familial breast and ovarian cancer have shown that several genes involved in a cellular DNA repair pathway called "homologous recombination" are involved in cancer susceptibility.  For example, mutations in BRCA1, BRCA2, and RAD51C that can lead to Hereditary Breast and Ovarian Cancer risk can screw up DNA repair by homologous recombination within human cells.

It turns out that several other human genes code for proteins involved in homologous recombination within the cell, and it doesn't take a rocket scientist to guess that these genes might be involved in cancer risk too.  However, proving it is much easier said than done.

 Dr. Rahman and her colleagues were able to pull this off, however, thanks to access to DNA from a very large number of families with multiple cases of breast and ovarian cancer who had given permission for research.  They ruled out BRCA1 or BRCA2 mutations as a cause in the families in the current study.

Because the RAD51D gene is quite similar to RAD51C (they are called "paralogs" of each other in scientific terms), Dr. Rahman and her colleagues decided to look for mutations in RAD51D in the families without BRCA1/2 mutations.  What they found clearly establishes RAD51D in the group of genes behind familial ovarian cancer:

1. They found what look to be important "inactivating" RAD51D mutations in individuals from 8 of 911 families (0.9%) with at least 1 family ovarian cancer case and at least 1 family breast cancer case.  (A mutation was found in 1 out of 1,060 control individuals from families without breast and ovarian cancer family history)
   
2. Families in which the family history of cancer was most suggestive of cancer were more likely to have a RAD51D mutation.  1.7% of families with two or more cases of ovarian cancer had a RAD51D mutation.  For families with three or more cases of ovarian cancer, 5.1% had a RAD51D mutation.
3. When they studied other individuals with cancer in the families in which an initial person was found to have a RAD51D mutations, five out of five individuals affected with ovarian or breast cancer were found to have the family mutation.  This is consistent with the cancer risk potentially being due to the RAD51D mutation throughout the family. 
   
4. Using a statistical technique called "modified segregation analysis," they were able to show that ovarian cancer risk for carriers of the RAD51D mutations was approximately 6.3-fold higher than average risk. 
   
5. Female RAD51D mutation carriers were estimated to have a lifetime risk of ovarian cancer of approximately 10% as compared to the typical woman's lifetime ovarian cancer risk of about 1.5%.
6. There were too few breast cancer cases in the families with RAD51D mutations to be able to say with statistical certainty that there is any relationship between RAD51D mutations and breast cancer risk.  Thus, for now, we can only say for sure that RAD51D mutations confer ovarian cancer risk.  Future studies may further address questions about whether RAD51D mutations might be associated with risk of breast or other cancers.
7. Given recent evidence suggesting that cancer patients with BRCA1 or BRCA2 mutations may benefit in some cases from treatment with the homologous recombination pathway-targeting PARP inhibitor class of drugs, they assessed whether there was evidence in vitro that PARP inhibitor olaparib (AstraZeneca) selectively killed cells with reduced RAD51D activity.  The answer was yes, suggesting that PARP inhibitors may be useful in the treatment of cancers in individuals with RAD51D mutations.

 

Bottom Line Implications

1. Mutations in the RAD51D gene are responsible for ovarian cancer susceptibility in some families in which the familial risk of ovarian cancer is not explained by mutations in BRCA1 or BRCA2.
2. Although this is very important progress, this only explains ovarian cancer risk in a small subset of families.
3. Future studies will investigate risk of other cancers in families in which ovarian cancer risk is due to RAD51D mutations.
4. Preliminary evidence from in vitro experiments suggests that future clinical studies should assess whether PARP inhibitors may be particularly effective in the treatment of cancer in individuals with RAD51D mutations.

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Selected References

Loveday C, Turnbull C, Ramsay E, et al.  Germline mutations in RAD51D confer susceptibility to ovarian cancer.  Nature Genetics 2011 (Published online August 7 2011)

Mechanism of Cisplatin-Resistance in BRCA2-Related Ovarian Cancers

Our increasing molecular knowledge of the pathways involved in cancer development continues to suggest potential avenues for molecularly-targeted cancer therapies.  However, aside from a few examples (Gleevec, Herceptin, and others), molecularly-targeted therapy is still not a reality for most cancer types.

Individuals born with mutations in the BRCA2 gene have a substantially elevated lifetime risk for breast cancer, ovarian cancer, and several other cancers.  Recent work has shown that loss of BRCA2 function results in defects in a DNA repair process called "homologous recombination."  Evidence has emerged that PARP-inhibitor drugs, which are currently under development as possible treatments for BRCA2-associated cancers, are potent killers in vitro of cells lacking BRCA2.  In fact, the loss of homologous recombination capacity in BRCA2 mutant cells is thought to be an achilles heel that may be exploited both by PARP-inhibitors and also by platinum compounds such as cisplatin (BRCA2-mutated ovarian cancers seem to be particularly sensitive to cisplatin). 

However, individuals treated with another molecularly-targeted therapy, Gleevec, for chronic myelogenous leukemia have developed resistance to the drug in some cases.  Indeed, individuals with BRCA2-related ovarian cancers ultimately develop cisplatin resistance. 

Two papers published online today in the journal Nature (abstracts available here and here) show us why this is the case at least in a subset of cases in individuals with BRCA2 mutations.  Basically, various revertent mutations can occur under selection of cisplatin or PARP-inhibitors that result in expression of a functional BRCA2 protein again that improves the cellular capacity to promote homologous recombination, thus eliminating the achilles heel.  Thus, BRCA2 loss is involved in the establishment of the cancer, but is not necessary for its maintenance (especially under the selective pressure of treatment with Cisplatin).

This has a number of implications:

• Genotyping of tumors in individuals with BRCA2 mutations may help to predict whether PARP-inhibitors or platinum-containing compounds are likely to be effective in their treatment
• BRCA2-associated tumors that have acquired PARP/cisplatin-resistance may be treatable with a combination of cisplatin or a PARP-inhibitor plus a secondary drug disrupting homologous recombination
• Although PARP-inhibitors have not yet reached the clinic, we now know of one potential challenge in their potential use
• As some sporadic ovarian cancers seem to have lost BRCA2 function, these findings may be relevant to understanding treatment resistance even in some ovarian cancers that apparently are not hereditary