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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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

More on the Woman Who Filed an EEOC Complaint Claiming She Was Fired Over a Genetic Test Revealing a BRCA2 Mutation

The internet is abuzz with all kinds of information related to the case that we discussed yesterday here inovolving a Connecticut woman, Pamela Fink, who has filed a complaint with the EEOC and others alleging genetic discrimination under GINA (Genetic Information Nondiscrimination Act) .  She states that her former employer, MXenergy, fired her because of a genetic test that revealed that she carried a mutation in the BRCA2 gene, which confers very high lifetime risks of breast and ovarian cancer. 

Video is beginning to emerge (thanks to Nature News for pointing us in this direction) with more information about the case. 

Here is a piece from Fox61 News via courant.com:

 

 

 

Additionally, in another Fox news piece (posted along with the one above over at Nature News), Ms. Fink and her lawyer discuss the case.  She mentions that two of her sisters are cancer survivors.  This is not surprising in light of her decision to pursue prophylactic mastectomy, as women with close family members affected by breast cancer are more likely to pursue the preventative surgery in the context of a BRCA1 or BRCA2 mutation. 

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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

RAD51C: A New Hereditary Breast and Ovarian Cancer Gene

If you have a compelling family history of breast and ovarian cancer that is not explained by a mutation in the BRCA1 or BRCA2 gene, it is possible that the RAD51C gene could be the explanation.  An international research team demonstrated that mutations in RAD51C can lead to hereditary breast and ovarian cancer risk in a paper published online in Nature Genetics yesterday.

"Biallelic" RAD51C Mutations Cause a Fanconi Anemia-Like Disorder

On Sunday at DNA and You, we covered the demonstration by an international team that biallelic mutations of the RAD51C gene can cause a Fanconi anemia-like disorder in children.  In other words, children who inherit two mutated copies of RAD51C from each of two carrier parents develop Fanconi anemia (or at least something that closely resembles it).  

This was a critical clue that led some of the same investigators to assess the role of RAD51C in hereditary breast and ovarian cancer not caused by mutations in the BRCA1 and BRCA2 genes.   

RAD51C is a Breast and Ovarian Cancer Susceptibility Gene

Work over the last several years has demonstrated a number of molecular and genetic connections between Hereditary Breast and Ovarian Cancer (HBOC) susceptibility and Fanconi anemia.  Women with a single disease-causing mutation in BRCA2 have a substantially increased risk of breast and ovarian cancer.  A key insight came when it was demonstrated in 2002 that a subset of Fanconi anemia - a condition characterized by multiple congenital anomalies, bone marrow failure leading to abnormal blood cell counts, and susceptibility to leukemia and other cancers - was due to inherited mutations in BRCA2 (in these cases, the children had two mutations in BRCA2 - one inherited from each parent). 

Subsequently, a cellular network of interacting proteins implicated in Fanconi anemia (including BRCA2) that collaborate in DNA repair has emerged.  Interestingly, several of these proteins are coded for by genes that can increase susceptibility to breast and/or ovarian cancer in individuals inheriting a single mutated gene (as opposed to two mutated genes which leads to Fanconi anemia).  These include BRCA2 (FA subtype-D1), BRIP1 (FA subtype-J), and PALB2 (FA subtype-N). 

Due to the strong molecular and genetic connections between Fanconi anemia and hereditary breast and ovarian cancer susceptibility, the team that reported that RAD51C mutations could cause a Fanconi anemia-like condition decided to investigate whether female carriers of single RAD51C mutations might be at elevated risk for breast and/or ovarian cancer. 

To answer this question, they worked with the German Consortium for Hereditary Breast and Ovarian Cancer, which had recruited individuals from 1100 German families that appeared to have hereditary gynecologic malignancies via clinical cancer genetics programs at five centers in Germany (Cologne, Dresden, Dusseldorf, Munich, and Ulm).  620 of these were "breast cancer pedigrees" - that is there were at least three affected females with breast cancer, but no ovarian cancers in the family.  In the other 480 families, at least one case of breast cancer and one case of ovarian cancer had occured.  The team also had ruled out the possibility in these women that the cancer susceptibility was caused by either mutations or rearrangements of the known hereditary breast and ovarian cancer susceptibility genes BRCA1 and BRCA2.  Thus, these were families with clustering of breast cancer or breast/ovarian cancer that was genetically unexplained.

No significant mutations were found in RAD51C in the 620 families with breast cancer only.  However, when they looked at the breast and ovarian cancer families, things got really interesting.  In all, they were able to identify a total of 6 mutations in the 480 families that had sufficient evidence to implicate them in the breast and ovarian cancer susceptibility.  Thus, in this German study of women with unexplained familial breast and ovarian cancer, the cancer susceptibility in 1.3% of the families could be explained by heterozygous mutations in the RAD51C gene.

Some Implications

1. This adds to the long list of connections between the Fanconi anemia cellular DNA repair pathway and breast and ovarian cancer susceptibility.  Although we still do not understand this pathway well at a cellular and molecular level, future efforts in this area could lead to future successes with molecularly targeted therapy.  We'll write more about this soon.

2. This lends more support to the concept that rare mutations may substantially impact breast cancer risk and ultimately be shown to account for a significant chunk of the "missing heritability" of breast cancer (i.e., the fraction of the heritable component of breast cancer risk that is unexplained by currently known genetic factors).  It's clear though that a combination of rare high penetrance mutations in genes like BRCA1, BRCA2 and TP53; rare moderate penetrance mutations in genes like ATM, BRIP1 and PALB2; and common low-penetrance breast cancer susceptibility single nucleotide polymorphisms (where it is generally still not clear what the underlying functionally significant genetic change is) all have an impact on breast cancer risk.  Hopefully, the widespread availability and dropping cost of next generation sequencing will lead us to more of the rare genes in the not too distant future. 

3. It's clear that there are other causes of hereditary breast and ovarian cancer besides BRCA1 and BRCA2 - particularly in families with very impressive family histories of breast and ovarian cancer but no BRCA1/2 mutations.  RAD51C mutations can now be added to that list.  In general, unless there is something particularly compelling about the family history that points in the direction of a specific syndrome (i.e., Li-Fraumeni Syndrome, Cowden Syndrome, Hereditary Diffuse Gastric Carcinoma Syndrome, or Peutz-Jeghers Syndrome) that could explain the breast cancer in a given family, physicians and genetic counselors in cancer genetics clinics currently don't generally search for mutations in the other genes that are rare causes.  With the falling cost of high throughput sequencing, this will change.  We'll write more about this in the near future.

4. In this study, the mutations completely segregated with the family with disease.  This has not always been the case in families with carriers of ATM, BRIP1, CHEK2, and PALB2 mutations.  Thus, although it is still too early to know for sure, RAD51C is perhaps leading to a clinical picture that is more similar to BRCA1 and BRCA2 than in these other examples (i.e., higher penetrance and both breast and ovarian cancer).  It will be interesting to see if the molecular explanation can be worked out - perhaps providing some clues towards future therapeutic strategies.  

5. This provides further support for the concept that other breast and/or ovarian cancer susceptibility genes may be found in the future amongst the set of genes coding for proteins that bind to Fanconi anemia pathway members and participate in DNA repair. Of note, a single nucleotide polymorphism (SNP) near the gene RAD51L1, another member of the RAD51 gene family like RAD51C, was recently found in a genome wide association study to have a modest, but statistically significant, association with breast cancer risk.  The implication of RAD51C in hereditary breast and ovarian cancer susceptibility makes me wonder even more whether the association of the RAD51L1 SNP with breast cancer risk might be explained by a nearby mutation in the actual RAD51L1 gene (coding sequence) in a subset of the cases studied.

Update (Aug. 7, 2011) - A paper published online today in Nature Genetics implicates the paralog of RAD51C, RAD51D, as a hereditary ovarian cancer risk gene. 

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Selected References

Meindl A, Hellebrand H, Wiek C, et al.  Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene.  Nature Genetics 2010; published online 18 April 2010; doi:10.1038/ng.569

Vaz F, Hanenberg H, Schuster B, et al.  Mutation of the RAD51C gene in a Fanconi anemia-like disorder.  Nature Genetics 2010; published online 18 April 2010; doi:10.1038/ng.570

Howlett NG, Taniguchi T, Olson S, et al.  Biallelic inactivation of BRCA2 in Fanconi anemia.  Science 2002; 297:606-9.

Moldovan GL, D'Andrea AD.  How the Fanconi anemia pathway guards the genome.  Annual Review of Genetics 2009; 43:223-49.

Levitus M, Waisfisz Q, Godthelp BP, et al.  The DNA helicase BRIP1 is defective in Fanconi anemia complementation group J.  Nature Genetics 2005; 37:934-5.

Levran O, Attwooll C, Henry RT, et al.  The BRCA1-interacting helicase BRIP1 is deficient in Fanconi anemia.  Nature Genetics 2005; 37:931-3.

Reid S, Schindler D, Hanenberg H, et al.  Biallelic mutations in PALB2 cause Fanconi anemia subtype FA-N and predispose to childhood cancer.  Nature Genetics 2007; 39:162-4.

Xia B, Dorsman JC, Ameziane N, et al.  Fanconi anemia is associated with a defect in the BRCA2 partner PALB2.  Nature Genetics 2007; 39:159-61.

Seal S, Thompson D, Renwick A, et al.  Truncating mutations in the Fanconi anemia J gene BRIP1 are low-penetrance breast cancer susceptibility alleles.  Nature Genetics 2006; 38:1239-41.

Erkko H, Xia B, Nikkila J, et al.  A recurrent mutation in PALB2 in Finnish cancer families.  Nature 2007; 446:316-19.

Rahman N, Seal S, Thompson D, et al.  PALB2, which encodes a BRCA2-interacting protein, is a breast cancer susceptibility gene.  Nature Genetics 2007; 39:165-7.

Stratton MR and Rahman N.  The emerging landscape of breast cancer susceptibility.  Nature Genetics 2008; 40:17-22.

Rahman N and Scott RH.  Cancer genes associated with phenotypes in monoallelic and biallelic mutation carriers: new lessons from old players.  Human Molecular Genetics 2007; 16:R60-6.

Turnbull C, Rahman N.  Genetic predisposition to breast cancer: past, present, and future.  Annual Review of Genomics and Human Genetics 2008; 9:321-45.

Walsh T, Casadei S, Coats KH, et al. Spectrum of mutations in BRCA1, BRCA2, CHEK2, and TP53 in families at high risk of breast cancer.  JAMA 2006; 295:1379-88.