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)

Family History of Cancer Changes Over Time: Why You Need to Keep Your Primary Care Doctor Updated

If you are interested in cancer prevention, you may know that for common cancers family history is one of the most important and useful tools that we have to identify people at elevated risk (who are likely to benefit most from more intensive screening and/or preventative measures).

Despite this fact, discussion of family history often gets lost in the shuffle in primary care - which is not surprising given how much stuff today's healthcare providers need to pack into a visit that often may only last 10 minutes or so.   That said, many healthcare providers are doing a better job of asking about a family history of cancer, but it is usually a static, one-time assessment that may happen most at the time of initiation of primary care with a new doctor.

A newly published research article by Argyrios Ziogas, Nora Horick, Sharon Plon, Dianne Finkelstein and colleagues from the Cancer Genetics Network (CGN) in JAMA provides evidence and analysis that suggests that doctors and patients should also pay more attention to changes in family history of cancer over time.

Ziogas and colleagues used a couple of different analytical approaches to try to find answers to this question:

How often do family cancer histories change enough over time that they would merit changes in the intensity of screening based on American Cancer Society guidelines?

They focused on 3 of the most common cancer types: breast cancer, colorectal cancer, and prostate cancer.  Although there are a few caveats, in general, their results suggest that it is well worth it for people to make sure that their doctors are aware of any changes in their cancer history.

In the case of breast cancer, their results suggest that about 4 percent of women will have a change in their family history of cancer between the ages of 30 and 50 sufficient to suggest that they are in a somewhat higher risk group that may benefit from breast MRI screening (per American Cancer Society Guidelines). 

For colorectal cancer, their results suggest that about 5 percent of people will have a change in their family history of cancer between ages 30 and 50 that suggests that a more aggressive colonoscopy screening strategy may be warranted (per American Cancer Society Guidelines).

The impact of prostate cancer family history changes was less impressive. 

Overall, it seems clear that in the clinic we need to think of cancer family history as the often changing entity that it is, rather than the static, never changing, thing that may get entered in the clinic chart at the first visit and then never re-visited.

 What You Can Do: If someone in your family is newly diagnosed with cancer (parents, brothers, sisters, children, aunts, uncles, grandparents, cousins), let your physicians and other healthcare providers know about it the next time you see them.  This way, they can update the family history that they have on file for you and consider whether the information might suggest that you should have more intensive cancer screening.

Cited Reference

Ziogas A, Horick NK, Kinney AY, et al.  Clinically relevant changes in family history of cancer over time.  JAMA 2011; 306:172-8. 

Further Reading

Acheson LS.  Recording, interpreting, and updating the family history of cancer: implications for cancer prevention.  JAMA 2011; 306:208-10.

Qureshi N, Wilson B, Santaguida P, et al.  Collection and use of cancer family history in primary care: Evidence Report/Technology Assessment No. 159.  Rockville, MD: Agency for Healthcare Research and Quality, 2007.  AHRQ Publication 08-E001.

Scheuner MT, McNeel TS, Freedman AN.  Population prevalence of familial cancer and common hereditary cancer syndromes: the 2005 California Health Interview Survey.  Genet Med 2010; 12:726-35.

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Know someone with Hereditary Breast and Ovarian Cancer risk due to a BRCA1 or BRCA2 mutation?  Encourage them to check out BRCAscoop.com - a new high quality health information resource focused on newly published evidence related to cancer prevention, screening and treatment for people with BRCA1 or BRCA2 mutations

New Financial Assistance Program for Young Women with BRCA1 and BRCA2 Mutations Needing Help Paying for Screening Breast MRI

In a previous post we mentioned a Christina Applegate appearance on Oprah to discuss both learning that she (Ms. Applegate) had Hereditary Breast and Ovarian Cancer risk due to a BRCA1 mutation and the aftermath.  Since then, The Christina Applegate Foundation has worked to promote awareness of the importance of breast MRI screening for high-risk women.  However, one key impediment for some women is the cost of MRI.  Now, Right Action for Women is doing something to address this problem. 

Right Action for Women and Patient Services, Inc. recently partnered to deliver a new financial assistance program aimed at young women at high-risk for breast cancer needing assistance with the cost of screening breast MRI (link is to more info at BRCAscoop.com).

Tony Snow, Former Bush Press Secretary, Dies at 53: A Reminder About Familial Colon Cancer and Opportunities for Prevention

Tony Snow, the conservative writer, commentator, and former Bush administration Press Secretary, died on the morning of July 12 at the age of 53 of colorectal cancer. 

It's worth mentioning that Mr. Snow had a family history of colon cancer, as his mother apparently died of the disease when he was 17 years old.  As Mr. Snow has publicly acknowledged a diagnosis of ulcerative colitis (UC), it seems most likely that the cancer in his family is related to UC, rather than to what are arguably the two most important hereditary cancer predisposition syndromes for colon cancer, Lynch syndrome (aka hereditary non-polyposis colorectal cancer or HNPCC) and familial adenomatous polyposis (FAP).

The lifetime risk for colon cancer in individuals at average risk in the United States is about 5 percent.  Nine out of ten cases occur after the age of 50.  Individuals with ulcerative colitis have a ~3- to 12-fold elevated risk of developing colon cancer depending on the extent of colon involvement and the length of time the disease has been present.  Ulcerative colitis risk is influenced by genetics, but the inheritance is complex, without major deterministic susceptibility genes like those for FAP (APC) and Lynch syndrome (MLH1, MSH2, MSH6, PMS2). 

Mr. Snow's death is an opportunity to remind folks that colon cancer, in general, is a highly preventable disease.  Stay tuned to future posts for more details.

Where You Get Your Mammogram Matters!

A research group led by Dr. Stephen Taplin of the National Cancer Institute has published a paper in the June 18th issue of the Journal of the National Cancer Institute that assesses whether certain factors differing between mammography facilities are associated with better interpretive accuracy on screening mammograms.

The bottom line is that there are several things that were signficant.  Sensitivity, the ability to detect breast cancers, was quite high and varied little.  However, specificity and positive predictive value varied significantly between sites.  Thus, it seems that the degree to which sites may be "overcalling" their reads (presumably to avoid missing something) varies. 

The following mammography facility traits were associated with better interpretive accuracy for screening mammography:

• Performing only screening mammography at the facility (as opposed to screening plus diagnostic mammography)
• Having a breast imaging specialist interpreting the mammograms
• Not performing double reading of mammograms (more false positives when read by more than one radiologist)
• Conducted audit reviews 2 or more times per year (where individual radiologist-level performance data is shared with the radiologist)

The authors note that it was surprising that double reading did not improve overall test accuracy and that this contrasts with the results of randomized clinical trials.  It may be that double reading methods differ or have been implemented differently in typical clinical practice environments outside of clinical trials.  This deserves a closer look in the future.  Given the relatively weak effect of this predictor of performance, the authors suggested that it should not be utilized to differentiate amongst facility performance until further detailed research is done to sort out the controversy.

It is important to keep in mind that the above factors affected specificity and positive-predictive value primarily.  The authors point out that whether sensitivity or specificity is most important in picking a mammogram facility is dependent on a value judgment.  That is, some women may be most concerned about sensitivity at all costs (i.e., a higher false positive rate leading to a biopsy does not matter).  Other women may wish to consider factors like those noted above that affect specificity and positive predictive value (i.e., they would like to avoid unnecessary biopsies while keeping sensitivity high). 

The results of this retrospective study should be confirmed elsewhere before they are utilized for decision-making.  Nevertheless, you may want to have a dialogue with your physician about mammography facility choice.