Editors' ChoiceHuman Genetics

A BRCA3 Gene?

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Science Translational Medicine  28 Apr 2010:
Vol. 2, Issue 29, pp. 29ec67
DOI: 10.1126/scitranslmed.3001196

Fanconi’s anemia (FA) is the most common heritable cause of bone marrow failure. This predominantly autosomal recessive chromosomal instability disorder typically occurs exclusively in carriers of a homozygous mutation in one of 13 known candidate genes. Coincidentally, these genes are critically involved in the same DNA damage–response pathways as the well-known breast and ovarian cancer susceptibility genes BRCA1, BRCA2, PALB2, and BRIP1.

Now, Meindl et al. and Mathews et al. identify new FA, breast, and ovarian cancer-susceptibility variants in another gene, RAD51C, that is also involved in the DNA double-strand break repair process. In the first study, linkage analysis of a single consanguine family afflicted with FA identified a biallelic protein–altering mutation in the RAD51C gene that explained the root cause of disease in this family. Rigorous functional assays of leukocytes and fibroblasts transfected with wild-type and RAD51C mutant genes supported their hypothesis. Then the authors extensively sequenced the RAD51C gene in 1100 pedigrees of breast and ovarian cancer with the goal of identifying monoallelic cancer–causing variants. Remarkably, protein-altering mutations in RAD51C were confirmed in six pedigrees, with tumors isolated from these cancer patients demonstrating a complete loss of heterozygosity. In addition, no healthy woman greater than 70 years of age in the affected pedigrees carried any of the RAD51C oncogenic mutations. The average age of onset of 53 for breast cancer and 60 for ovarian cancer is highly consistent with that seen in individuals harboring BRCA2 mutations and certainly much earlier than seen with sporadic cases. Further, the observed RAD51C mutation prevalence of 1.5% in breast and ovarian cancer pedigrees, the role of the gene in DNA double-strand break repair, and the loss of heterozygosity seen in the breast and ovarian tumors are all consistent with the effects of the well-established oncogenes BRCA1 and BRCA2. As whole-genome and exome sequencing becomes increasingly common, these results ensure that in addition to the BRCA genes, oncologists will also be looking closely for cancer-causing mutations in this new BRCA-like oncogene.

A. Meindl et al., Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat. Gen. 18 April 2010 (10.1038/ng.569). [Full Text]

F. Vaz et al., Mutation of the RAD51C gene in Fanconi anemia–like disorder. Nat. Gen. 18 April 2010 (10.1038/ng.570). [Abstract]

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