Deleterious RAD51C germline mutations rarely predispose to breast and ovarian cancer in Pakistan
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RAD51C plays a key role in homologous recombination-mediated DNA repair and maintenance of genomic stability. Biallelic RAD51C mutations cause Fanconi anemia, and monoallelic mutations predispose women to breast and ovarian cancer. Genetic variability of RAD51C and its impact in Asian populations have been poorly studied. Here, we report the results of comprehensive mutational screening of the RAD51C gene in 348 BRCA1/2-negative breast and/or ovarian cancer patients from Pakistan. Mutation analysis of the complete RAD51C-coding region was performed using denaturing high-performance liquid chromatography analysis, followed by DNA sequencing of variant fragments. Three novel protein-truncating mutations, c.204T>A, c.225T>G, and c.701C>G, were identified. c.204T>A was found in one out of 22 (4.5 %) early-onset (≤45 years of age) ovarian cancer patients and c.225T>G in one out of 119 (0.8 %) patients from breast cancer only families. c.701C>G was found in a 60-year-old control with no family history of breast/ovarian cancer. Furthermore, three novel in silico-predicted potentially functional mutations, a missense mutation, c.873T>G, a variant in 5′UTR, c.1-34T>G, and a recurrent intronic variant, c.965+21A>G, were identified. The missense mutation was observed in a patient with bilateral breast cancer from a breast and ovarian cancer family (HBOC), the 5′UTR variant was noted in an early-onset breast cancer patient, and the intronic variant in one early-onset breast cancer patient and one ovarian cancer patient from a HBOC family. Five of the six mutations described were not detected in 400 healthy controls. These findings suggest that RAD51C plays a marginal role in breast and ovarian cancer predisposition in Pakistan. Reliable estimation of the clinical implications of carrying a deleterious RAD51C mutation will require identification of additional mutation-positive patients/families.
KeywordsRAD51C Germline mutations Familial breast and/or ovarian cancer Pakistan
We are grateful to all family members for their participation in this study. This study was supported by the Shaukat Khanum Memorial Cancer Hospital and Research Centre and the German Cancer Research Center.
Conflict of interest
The authors declare that they have no conflicts of interest.
- 4.Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V, Neveling K, Endt D, Kesterton I, Autore F, Fraternali F, Freund M, Hartmann L, Grimwade D, Roberts RG, Schaal H, Mohammed S, Rahman N, Schindler D, Mathew CG (2010) Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42(5):406–409PubMedCrossRefGoogle Scholar
- 5.Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H, Ramser J, Honisch E, Kubisch C, Wichmann HE, Kast K, Deissler H, Engel C, Muller-Myhsok B, Neveling K, Kiechle M, Mathew CG, Schindler D, Schmutzler RK, Hanenberg H (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42(5):410–414PubMedCrossRefGoogle Scholar
- 7.De Leeneer K, Van BM, De BS, Swietek N, Schietecatte P, Sabbaghian N, Van den EJ, Willocx S, Storm K, Blaumeiser B, van Asperen CJ, Wijnen JT, Leunen K, Legius E, Michils G, Matthijs G, Blok MJ, Gomez-Garcia E, De PA, Tischkowitz M, Poppe B, Claes K (2012) Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing. Breast Cancer Res Treat 133(1):393–398PubMedCrossRefGoogle Scholar
- 10.Wong MW, Nordfors C, Mossman D, Pecenpetelovska G, Very-Kiejda KA, Talseth-Palmer B, Bowden NA, Scott RJ (2011) BRIP1, PALB2, and RAD51C mutation analysis reveals their relative importance as genetic susceptibility factors for breast cancer. Breast Cancer Res Treat 127(3):853–859PubMedCrossRefGoogle Scholar
- 15.Thompson ER, Boyle SE, Johnson J, Ryland GL, Sawyer S, Choong DYH, kConFab, Chenevix-Trench G, Trainer AH, Lindeman GJ, Mitchell G, James PA, Campbell IG (2012) Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Hum Mutat 33(1):95–99PubMedCrossRefGoogle Scholar
- 17.Vuorela M, Pylkas K, Hartikainen JM, Sundfeldt K, Lindblom A, von Wachenfeldt WA, Haanpaa M, Puistola U, Rosengren A, Anttila M, Kosma VM, Mannermaa A, Winqvist R (2011) Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility. Breast Cancer Res Treat 130(3):1003–1010PubMedCrossRefGoogle Scholar
- 24.Schnurbein G, Hauke J, Wappenschmidt B, Weber-Lassalle N, Engert S, Hellebrand H, Garbes L, Becker A, Neidhardt G, Rhiem K, Meindl A, Schmutzler RK, Hahnen E (2013) RAD51C deletion screening identifies a recurrent gross deletion in breast cancer and ovarian cancer families. Breast Cancer Res 15(6):R120PubMedCentralPubMedCrossRefGoogle Scholar
- 26.Chan PA, Duraisamy S, Miller PJ, Newell JA, McBride C, Bond JP, Raevaara T, Ollila S, Nystrom M, Grimm AJ, Christodoulou J, Oetting WS, Greenblatt MS (2007) Interpreting missense variants: comparing computational methods in human disease genes CDKN2A, MLH1, MSH2, MECP2, and tyrosinase (TYR). Hum Mutat 28(7):683–693PubMedCrossRefGoogle Scholar