RAD51C Mutation Panel 

RAD51C overview:
  • Breast cancer susceptible genes such as BRCA1, BRCA2, RAD51C are the essential genes that regulate genomic stability by Homologous Recombination (HR) pathway of DNA repair and any mutation in these genes will lead to genomics instability and thereby causes cancer[1&2].
  • The RAD51C HR dysfunction may similarly cause chromosomal rearrangements leading to breast and ovarian cancer susceptibility.
  • The RAD51C-dependent CHK2 activation reveals a novel role of RAD51C in DNA damage response and checkpoint function[3].
  • RAD51C loci in breast cancer patients suggest a critical role of RAD51C in tumor suppressor function[4].
RAD51C mutations and Cancer:
  • Inactivation of the RAD51C mutations have been observed exclusively in familial breast and ovarian cancers[5-7].
  • Missense mutation of RAD51C was identified in individuals presenting Fanconi-anemia syndrome[8].
  • The first evidence of RAD51C mutation leading to rare human genetic disorder and cancer[9].
  • Further supported by the fact that mice knockout of RAD51C is embryonically lethal and show suppression of tumor formation similar to TP53.
  • Other than breast cancer, a biallelic mutation of RAD51C is known to be observed in a family with several abnormalities of Fanconi-anemia[10].
  • Mutations in RAD51C are rare mutations that predispose to ovarian cancer, as well as to breast cancer but only in families with ovarian cancer[11].
 
RAD51C mutation risk factors in breast cancer:
  • RAD51C mutation increases the risk for breast and ovarian cancer, and was first established as a human cancer susceptibility gene[12].
  • RAD51C mutations that were identified in FA, breast and ovarian cancer patients reveal that there are independent HR functions of RAD51C in FA and BRCA pathway[13].
  • RAD51C mutation had a 5.2-fold increased risk of ovarian cancer, indicating that RAD51C is a moderate ovarian cancer susceptibility gene[14].
  • RAD51C mutations appear to be rare mutations that predispose to ovarian cancer, as well as to breast cancer but only in families with ovarian cancer.
  • A pathogenic mutation of RAD51C was present in approximately 1% to 3% of unselected ovarian cancers, and among mutation carriers, the lifetime risk of ovarian cancer was approximately 10-15% [15].
Recommended precautionary measures to watch for the development of cancer:
  • When a person is tested with RAD51C mutation, the physician highly recommends regular monitoring to check the development of the cancer.
  • There are research evidences that shows that monitoring plan improves the survival of individual with a RAD51C mutation who did not have any signs and symptoms of cancer.
  • Monthly breast self-examination, starting at the age of 18.
  • Clinical breast examination twice a year, annual breast MRI beginning at age 20 to 25.
References:
  1. Turnbull C, & Rahman N. (2008). Annu. Rev. Genomics Hum. Genet. 9:321–345.
  2. Ciccia A, McDonald N. & West SC. (2008). Annu. Rev. Biochem. 77:259–287.
  3. Badie S, et al. (2009). J. Cell Biol., 185:587-600.
  4. Kuznetsov SG, et al. (2009). Cancer Res, 69:863-872.
  5. Meindl A, Hellebrand H, Wiek C, et al., (2010). Nat Genet, 42(5):410–414),
  6. Romero A, Perez-Segura P, Tosar A, et al., (2011). Breast Cancer Res Treat, 129(3):939–946.
  7. Thompson ER, Boyle SE, Johnson J, et al., (2012). Hum Mutat, 33(1):95–99.
  8. Vaz F, Hanenberg H, Schuster B, et al., (2010). Nat Genet, 42(5):406–409.
  9. Meindl A, et al. (2010). Nat. Genet, 42:410-414.
  10. Vaz F, Hanenberg H, Schuster B, et al., (2010). Nat Genet, 42:406–409.
  11. Akbari MR, Tonin P, Foulkes WD, et al., (2010). Breast Cancer Res, 12: 404.
  12. Meindl A, Hellebrand H, Wiek C, et al., (May 2010). Nature Genetics, 42(5): 410–4.
  13. Kee Y, et al. (2010). Genes Dev. 24;1680-1694.
  14. Levy-Lahad E. (2010). Nat. Genet, 42:368-369.
  15. Song H, Dicks E, Ramus SJ, et al., (2015). Journal of Clinical Oncology, 33(26): 2901-7.