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.
