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Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing

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Abstract

Despite extensive analysis of the BRCA1 and BRCA2 genes, germline mutations are detected in <20% of families with a presumed genetic predisposition for breast and ovarian cancer. Recent literature reported RAD51C as a new breast cancer susceptibility gene. In this study, we report the analysis of 410 patients from 351 unrelated pedigrees. All were referred for genetic testing and we selected families with at least one reported case of ovarian cancer in which BRCA1&2 mutations were previously ruled out. We analyzed the coding exons, intron–exons boundaries, and UTRs of RAD51C. Our mutation analysis did not reveal any unequivocal deleterious mutation. In total 12 unique sequence variations were identified of which two were novel. Our study and others suggest a low prevalence of RAD51C mutations with an exception for some founder populations. This observation is in favor of the rare allele hypothesis in the debate over the nature of the genetic contribution to individual susceptibility to breast and ovarian cancer and further genome-wide studies in high risk families are warranted.

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References

  1. Ferlay J, Parkin DM, Steliarova-Foucher E (2010) Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer 46(4):765–781

    Article  PubMed  CAS  Google Scholar 

  2. O’Donovan PJ, Livingston DM (2010) BRCA1 and BRCA2: breast/ovarian cancer susceptibility gene products and participants in DNA double-strand break repair. Carcinogenesis 31(6):961–967

    Article  PubMed  Google Scholar 

  3. Ahlbom A, Lichtenstein P, Malmstrom H, Feychting M, Hemminki K, Pedersen NL (1997) Cancer in twins: genetic and nongenetic familial risk factors. J Natl Cancer Inst 89(4):287–293

    Article  PubMed  CAS  Google Scholar 

  4. Mack TM, Hamilton AS, Press MF, Diep A, Rappaport EB (2002) Heritable breast cancer in twins. Br J Cancer 87(3):294–300

    Article  PubMed  CAS  Google Scholar 

  5. Stratton MR, Rahman N (2008) The emerging landscape of breast cancer susceptibility. Nat Genet 40(1):17–22

    Article  PubMed  CAS  Google Scholar 

  6. Howlett NG, Taniguchi T, Olson S, Cox B, Waisfisz Q, De Die-Smulders C, Persky N, Grompe M, Joenje H, Pals G et al (2002) Biallelic inactivation of BRCA2 in Fanconi anemia. Science 297(5581):606–609

    Article  PubMed  CAS  Google Scholar 

  7. Levy-Lahad E (2010) Fanconi anemia and breast cancer susceptibility meet again. Nat Genet 42(5):368–369

    Article  PubMed  CAS  Google Scholar 

  8. Vaz F, Hanenberg H, Schuster B, Barker K, Wiek C, Erven V, Neveling K, Endt D, Kesterton I, Autore F et al (2010) Mutation of the RAD51C gene in a Fanconi anemia-like disorder. Nat Genet 42(5):406–409

    Article  PubMed  CAS  Google Scholar 

  9. Meindl A, Hellebrand H, Wiek C, Erven V, Wappenschmidt B, Niederacher D, Freund M, Lichtner P, Hartmann L, Schaal H et al (2010) Germline mutations in breast and ovarian cancer pedigrees establish RAD51C as a human cancer susceptibility gene. Nat Genet 42(5):410–414

    Article  PubMed  CAS  Google Scholar 

  10. Loveday C, Turnbull C, Ramsay E, Hughes D, Ruark E, Frankum JR, Bowden G, Kalmyrzaev B, Warren-Perry M, Snape K et al (2011) Germline mutations in RAD51D confer susceptibility to ovarian cancer. Nat Genet 43(9):879–882

    Article  PubMed  CAS  Google Scholar 

  11. Romero A, Perez-Segura P, Tosar A, Garcia-Saenz JA, Diaz-Rubio E, Caldes T, de la Hoya M (2011) A HRM-based screening method detects RAD51C germ-line deleterious mutations in Spanish breast and ovarian cancer families. Breast Cancer Res Treat 129(3):939–946

    Article  PubMed  CAS  Google Scholar 

  12. Thompson ER, Boyle SE, Johnson J, Ryland GL, Sawyer S, Choong DY, Kconfab, Chenevix-Trench G, Trainer AH, Lindeman GJ et al. (2011) Analysis of RAD51C germline mutations in high-risk breast and ovarian cancer families and ovarian cancer patients. Human mutation 12(66):433–43

  13. Akbari MR, Tonin P, Foulkes WD, Ghadirian P, Tischkowitz M, Narod SA (2010) RAD51C germline mutations in breast and ovarian cancer patients. Breast cancer research BCR 12(4):404

    Article  PubMed  Google Scholar 

  14. Zheng Y, Zhang J, Hope K, Niu Q, Huo D, Olopade OI (2010) Screening RAD51C nucleotide alterations in patients with a family history of breast and ovarian cancer. Breast Cancer Res Treat 124(3):857–861

    Article  PubMed  CAS  Google Scholar 

  15. Pang Z, Yao L, Zhang J, Ouyang T, Li J, Wang T, Fan Z, Fan T, Lin B, Xie Y (2011) RAD51C germline mutations in Chinese women with familial breast cancer. Breast Cancer Res Treat 129(3):1019–1020

    Article  PubMed  Google Scholar 

  16. Pelttari LM, Heikkinen T, Thompson D, Kallioniemi A, Schleutker J, Holli K, Blomqvist C, Aittomaki K, Butzow R, Nevanlinna H (2011) RAD51C is a susceptibility gene for ovarian cancer. Hum Mol Genet 20(16):3278–3288

    Article  PubMed  CAS  Google Scholar 

  17. Silvestri V, Rizzolo P, Falchetti M, Zanna I, Masala G, Palli D, Ottini L (2011) Mutation screening of RAD51C in male breast cancer patients. Breast cancer research BCR 13(1):404

    PubMed  Google Scholar 

  18. Vuorela M, Pylkas K, Hartikainen JM, Sundfeldt K, Lindblom A, von Wachenfeldt Wappling A, Haanpaa M, Puistola U, Rosengren A, Anttila M et al (2011) Further evidence for the contribution of the RAD51C gene in hereditary breast and ovarian cancer susceptibility. Breast Cancer Res Treat 130(3):1003–1010

    Article  PubMed  CAS  Google Scholar 

  19. Wong MW, Nordfors C, Mossman D, Pecenpetelovska G, Avery-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):853–859

    Article  PubMed  CAS  Google Scholar 

  20. Clague J, Wilhoite G, Adamson A, Bailis A, Weitzel JN, Neuhausen SL (2011) RAD51C germline mutations in breast and ovarian cancer cases from high-risk families. PLoS ONE 6(9):e25632

    Article  PubMed  CAS  Google Scholar 

  21. Walsh T, Casadei S, Lee MK, Pennil CC, Nord AS, Thornton AM, Roeb W, Agnew KJ, Stray SM, Wickramanayake A et al (2011) Mutations in 12 genes for inherited ovarian, fallopian tube, and peritoneal carcinoma identified by massively parallel sequencing. Proc Nat Acad Sci USA 108(44):18032–18037

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This research was supported by grant G.A044.10 from the Fund for Scientific Research Flanders (FWO), by GOA grant BOF10/GOA/019 (Ghent University). “Emmanuel van der Schueren” grant from the “Vlaamse Liga tegen Kanker” and by the Quebec Ministry of Economic Development, Innovation and Export Trade (MDEIE). Furthermore, the authors would like to thank Yvonne Detisch for her help with collecting the clinical information of the families of Maastricht.

Conflict of interest

The authors have no conflict of interest.

Author information

Authors and Affiliations

  1. Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium

    K. De Leeneer, M. Van Bockstal, S. De Brouwer, N. Swietek, P. Schietecatte, A. De Paepe, B. Poppe & K. Claes

  2. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, QC, Canada

    N. Sabbaghian & M. Tischkowitz

  3. Center for Medical Genetics, University Hospital of Antwerp, Antwerp, Belgium

    J. Van den Ende, S. Willocx, K. Storm & B. Blaumeiser

  4. Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands

    C. J. Van Asperen & J. T. Wijnen

  5. Department of Gynaecological Oncology, Catholic University of Leuven, Leuven, Belgium

    K. Leunen

  6. Department of Human Genetics, Catholic University of Leuven, Leuven, Belgium

    E. Legius, G. Michils & G. Matthijs

  7. Department of Clinical Genetics, Maastricht University Medical, Maastricht, The Netherlands

    M. J. Blok & E. Gomez-Garcia

  8. Department of Medical Genetics, University of Cambridge, Cambridge, UK

    M. Tischkowitz

Authors
  1. K. De Leeneer
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  2. M. Van Bockstal
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  3. S. De Brouwer
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  4. N. Swietek
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  5. P. Schietecatte
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  6. N. Sabbaghian
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  7. J. Van den Ende
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  8. S. Willocx
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  9. K. Storm
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  10. B. Blaumeiser
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  11. C. J. Van Asperen
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  12. J. T. Wijnen
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  13. K. Leunen
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  14. E. Legius
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  15. G. Michils
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  16. G. Matthijs
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  17. M. J. Blok
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  18. E. Gomez-Garcia
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  19. A. De Paepe
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  20. M. Tischkowitz
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  21. B. Poppe
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  22. K. Claes
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Corresponding author

Correspondence to K. Claes.

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De Leeneer, K., Van Bockstal, M., De Brouwer, S. et al. Evaluation of RAD51C as cancer susceptibility gene in a large breast-ovarian cancer patient population referred for genetic testing. Breast Cancer Res Treat 133, 393–398 (2012). https://doi.org/10.1007/s10549-012-1998-4

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  • DOI: https://doi.org/10.1007/s10549-012-1998-4

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