Cancer and Your Genes

Other Cancers Seen in Families with RAD51D Mutations

Two days ago, we discussed a recent study by Dr. Nazneen Rahman and colleagues which clearly demonstrated that inherited mutations in a gene called RAD51D result in a substantial elevation in risk for ovarian cancer.  Some families with mutations in the study also had some other cancer types in the family tree.  So, does this mean that the other cancer types in these families are also due to the RAD51D mutations?

In short, the answer is that we don't know.  Ovarian cancer risk was the only one that Dr. Rahman and her colleagues could pin down as being associated with RAD51D mutations with any statistical confidence.  For the others, future studies can address the specific question; however, they may be challenging and require extremely large sample sizes in order to have the statistical power to answer the question.

Here are the other cancer types that were seen in the eight families with inactivating RAD51D mutations in the study:

Breast Cancer

•  Seen in 8 out of 8 families (not surprising given that the families were included in the study because they had both ovarian and breast cancer)
• There were 13 breast cancer cases total in these 8 families
• Two of the breast cancer cases were bilateral
• Seven of the 13 cases were found to have inactivating RAD51D mutations (the other 6 were not tested)
• In contrast to ovarian cancer, the association of RAD51D mutations with breast cancer was not statistically significant (Relative Risk = 1.32 with 95% confidence intervals from 0.59 - 2.96)

Colorectal Cancer

•  Seen in 5 out of 8 families (keep in mind that some of these extended families are quite large and that colorectal cancer is common)
• There were 8 total colorectal cancer cases in the 5 families
• None of the affected individuals were tested for the presence of mutations in this study

Lung Cancer

•  Seen in 1 individual in 1 out of 8 families (keep in mind that some of these extended families are quite large and that lung cancer is common)
• The individual with lung cancer was not tested for the presence of the familial RAD51D mutation in this study

Non-Hodgkin Lymphoma

•  Seen in 1 individual in 1 out of 8 families
• The individual with NHL was not tested for the presence of the familial RAD51D mutation

Pancreatic Cancer

•  Seen in 2 individuals total from 2 out of 8 families
• The 2 individuals with pancreatic cancer were not tested for the familial RAD51D mutation

Prostate Cancer

• A total of 2 cases were seen in 1 out of the 8 families
• The 2 individuals with prostate cancer were not tested for the familial RAD51D mutation

It's very important to keep in mind that seeing these cancers in these families could just be due to chance or to the fact that the families were more likely to come to the researchers' attention because of the other cancers (particularly breast cancer).  Thus, we can't say anything about whether RAD51D mutations may lead to elevated risk for any cancer other than ovarian cancer based on this study.  Nevertheless, it will be important in the future to keep an eye on this. 

Bottom Line Implications

1. Mutations in the RAD51D gene lead to ovarian cancer risk in some families in which the familial ovarian cancer risk is not explained by mutations in BRCA1/2

2. Although several other cancer types (including breast cancer) were seen in the families with mutations, there was no statistically significant evidence from this study implicating RAD51D mutations in risk for any of the other cancer types. 

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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)

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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Was this helpful?  Would you like to be notified when we post other similar breast and ovarian cancer risk-related information?  Click here for our free newsletter updates!

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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)

New BRCA1 Single Molecule Sequencing Method Published

We just mentioned at BRCAscoop that a new paper in Genome Research from Helicos reports a new single molecule sequencing strategy for the BRCA1 gene that is discussed in a way that could leave one wondering whether they think they have a workaround for existing intellectual property.  It may be important that their single molecule sequencing method does not involve any DNA amplification.

As I am not a lawyer, I'm curious to see what folks with expertise in IP law will think about this.

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).