Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Short Communication
  • Published:

Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations

Subjects

Abstract

BRCA1 and BRCA2 are the two major genes predisposing to breast and ovarian cancer. Whereas high de novo mutation rates have been demonstrated for several genes, only 11 cases of de novo BRCA1/2 mutations have been reported to date and the BRCA1/2 de novo mutation rate remains unknown. The present study was designed to fill this gap based on a series of 12 805 consecutive unrelated patients diagnosed with breast and/or ovarian cancer who met the inclusion criteria for BRCA1/2 gene analysis according to French guidelines. BRCA1/2 mutations were detected in 1527 (12%) patients, and three BRCA1 mutations and one BRCA2 mutation were de novo. The BRCA1/2 de novo mutation rate was estimated to be 0.3% (0.1%; 0.7%). Although rare, it may be useful to take the possibility of de novo BRCA1/2 mutation into account in genetic counseling of relatives and to improve the understanding of complex family histories of breast and ovarian cancers.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2

Similar content being viewed by others

References

  1. Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavtigian S et al. A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994; 266: 66–71.

    Article  CAS  PubMed  Google Scholar 

  2. Wooster R, Bignell G, Lancaster J, Swift S, Seal S, Mangion J et al. Identification of the breast cancer susceptibility gene BRCA2. Nature 1995; 378: 789–792.

    Article  CAS  PubMed  Google Scholar 

  3. Mavaddat N, Peock S, Frost D, Ellis S, Platte R, Fineberg E et al. Cancer risks for BRCA1 and BRCA2 mutation carriers: results from prospective analysis of EMBRACE. J Natl Cancer Inst 2013; 105: 812–822.

    Article  CAS  PubMed  Google Scholar 

  4. Caputo S, Benboudjema L, Sinilnikova O, Rouleau E, Béroud C, Lidereau R et al. Description and analysis of genetic variants in French hereditary breast and ovarian cancer families recorded in the UMD-BRCA1/BRCA2 databases. Nucleic Acids Res 2012; 40: D992–D1002.

    Article  CAS  PubMed  Google Scholar 

  5. Tesoriero A, Andersen C, Southey M, Somers G, McKay M, Armes J et al. De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. Am J Hum Genet 1999; 65: 567–569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Edwards E, Yearwood C, Sillibourne J, Baralle D, Eccles D . Identification of a de novo BRCA1 mutation in a woman with early onset bilateral breast cancer. Fam Cancer 2009; 8: 479–482.

    Article  CAS  PubMed  Google Scholar 

  7. Kwong A, Ng EK, Tang EY, Wong CL, Law FB, Leung CP et al. A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer. Fam Cancer. 2011; 10: 233–237.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Garcia-Casado Z, Romero I, Fernandez-Serra A, Rubio L, Llopis F, Garcia A et al. A de novo complete BRCA1 gene deletion identified in a Spanish woman with early bilateral breast cancer. BMC Med Genet 2011; 12: 134.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. De Leeneer K, Coene I, Crombez B, Simkens J, Van den Broecke R, Bols A et al. Prevalence of BRCA1/2 mutations in sporadic breast/ovarian cancer patients and identification of a novel de novo BRCA1 mutation in a patient diagnosed with late onset breast and ovarian cancer: implications for genetic testing. Breast Cancer Res Treat 2012; 132: 87–95.

    Article  PubMed  Google Scholar 

  10. Delon I, Taylor A, Molenda A, Drummond J, Oakhill K, Girling A et al. A germline mosaic BRCA1 exon deletion in a woman with bilateral basal-like breast cancer. Clin Genet. 2013; 84: 297–299.

    Article  CAS  PubMed  Google Scholar 

  11. van der Luijt RB, van Zon PH, Jansen RP, van der Sijs-Bos CJ, Wárlám-Rodenhuis CC, Ausems MG . De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer. J Med Genet 2001; 38: 102–105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Robson M, Scheuer L, Nafa K, Ellis N, Offit K . Unique de novo mutation of BRCA2 in a woman with early onset breast cancer. J Med Genet 2002; 39: 126–128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hansen TV, Bisgaard ML, Jønson L, Albrechtsen A, Filtenborg-Barnkob B, Eiberg H et al. Novel de novo BRCA2 mutation in a patient with a family history of breast cancer. BMC Med Genet 2008; 9: 58.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Marshall M, Solomon S, Lawrence Wickerham D . Case report: de novo BRCA2 gene mutation in a 35-year-old woman with breast cancer. Clin Genet 2009; 76: 427–430.

    Article  CAS  PubMed  Google Scholar 

  15. Diez O, Gutiérrez-Enríquez S, Mediano C, Masas M, Saura C, Gadea N et al. A novel de novo BRCA2 mutation of paternal origin identified in a Spanish woman with early onset bilateral breast cancer. Breast Cancer Res Treat 2010; 121: 221–225.

    Article  CAS  PubMed  Google Scholar 

  16. Ripa R, Bisgaard ML, Bülow S, Nielsen FC . De novo mutations in familial adenomatous polyposis (FAP). Eur J Hum Genet 2002; 10: 631–637.

    Article  CAS  PubMed  Google Scholar 

  17. van Minkelen R, van Bever Y, Kromosoeto JN, Withagen-Hermans CJ, Nieuwlaat A, Halley DJ et al. A clinical and genetic overview of 18 years neurofibromatosis type 1 molecular diagnostics in the Netherlands. Clin Genet 2014; 85: 318–327.

    Article  CAS  PubMed  Google Scholar 

  18. Houdayer C, Gauthier-Villars M, Castéra L, Desjardins L, Doz F, Stoppa-Lyonnet D Retinoblastoma—genetic counseling and molecular diagnosis. In: Kumaramanickavel G (ed). Retinoblastoma: An Update on Clinical, Genetic Counseling, Epidemiology and Molecular Tumor Biology. InTech: Rijeka, Croatia, 2012, pp 55–73.

    Google Scholar 

  19. Bonaïti B, Alarcon F, Andrieu N, Bonadona V, Dondon MG, Pennec S et al. A new scoring system in cancer genetics: application to criteria for BRCA1 and BRCA2 mutation screening. J Med Genet 2014; 51: 114–121.

    Article  PubMed  Google Scholar 

  20. Zhang L, Fleischut MH, Kohut K, Spencer S, Wong K, Stadler ZK et al. Assessment of the prevalence of de novo mutations in the BRCA1 and BRCA2 genes. Clin Genet 2011; 80: 97–98.

    Article  CAS  PubMed  Google Scholar 

  21. Hodgkinson A, Eyre-Walker A . Variation in the mutation rate across mammalian genomes. Nat Rev Genet 2011; 12: 756–766.

    Article  CAS  PubMed  Google Scholar 

  22. Caux-Moncoutier V, Castéra L, Tirapo C, Michaux D, Rémon MA, Laugé A et al. EMMA, a cost- and time-effective diagnostic method for simultaneous detection of point mutations and large-scale genomic rearrangements: application to BRCA1 and BRCA2 in 1525 patients. Hum Mutat 2011; 32: 325–334.

    Article  CAS  PubMed  Google Scholar 

  23. Veltman JA, Brunner HG . De novo mutations in human genetic disease. Nat Rev Genet 2012; 13: 565–575.

    Article  CAS  PubMed  Google Scholar 

  24. Pal T, Keefe D, Sun P, Narod SA, Hereditary Breast Cancer Clinical Study Group. Fertility in women with BRCA mutations: a case-control study. Fertil Steril 2010; 93: 1805–1808.

    Article  CAS  PubMed  Google Scholar 

  25. Friedman E, Kotsopoulos J, Lubinski J, Lynch HT, Ghadirian P, Neuhausen SL . Spontaneous and therapeutic abortions and the risk of breast cancer among BRCA mutation carriers. Breast Cancer Res 2006; 8: R15.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Moslehi R, Singh R, Lessner L, Friedman JM . Impact of BRCA mutations on female fertility and offspring sex ratio. Am J Hum Biol 2010; 22: 201–205.

    PubMed  PubMed Central  Google Scholar 

  27. Antoniou AC, Pharoah PD, McMullan G, Day NE, Stratton MR, Peto J et al. A comprehensive model for familial breast cancer incorporating BRCA1 BRCA2 and other genes. Br J Cancer 2002; 86: 76–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Biesecker LG, Spinner NB . A genomic view of mosaicism and human disease. Nat Rev Genet 2013; 14: 307–320.

    Article  CAS  PubMed  Google Scholar 

  29. Walsh T, Lee MK, Casadei S, Thornton AM, Stray SM, Pennil C et al. Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing. Proc Natl Acad Sci USA 2010; 107: 12629–12633.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Antoniou AC, Easton DF . Models of genetic susceptibility to breast cancer. Oncogene 2006; 25: 5898–5905.

    Article  CAS  PubMed  Google Scholar 

  31. Tarabeux J, Zeitouni B, Moncoutier V, Tenreiro H, Abidallah K, Lair S et al. Streamlined ion torrent PGM-based diagnostics: BRCA1 and BRCA2 genes as a model. Eur J Hum Genet 2014; 22: 535–541.

    Article  CAS  PubMed  Google Scholar 

  32. Rouleau E, Lefol C, Tozlu S, Andrieu C, Guy C, Copigny F et al. High-resolution oligonucleotide array-CGH applied to the detection and characterization of large rearrangements in the hereditary breast cancer gene BRCA1. Clin Genet 2007; 72: 199–207.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This article is dedicated to the late Florence Copigny. We thank Isabelle Eugène, Catherine Gilbon, Karin Maciotta, Catherine Rougeron and Christine Lainé-Bidron for their helpful support during the course of this study.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to C Houdayer.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Golmard, L., Delnatte, C., Laugé, A. et al. Breast and ovarian cancer predisposition due to de novo BRCA1 and BRCA2 mutations. Oncogene 35, 1324–1327 (2016). https://doi.org/10.1038/onc.2015.181

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/onc.2015.181

This article is cited by

Search

Quick links