Skip to main content

Advertisement

SpringerLink
Log in

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

  • Preclinical study
  • Published:
Breast Cancer Research and Treatment Aims and scope Submit manuscript

Abstract

In order to adequately evaluate the clinical relevance of genetic testing in sporadic breast and ovarian cancer patients, we offered comprehensive BRCA1/2 mutation analysis in patients without a family history for the disease. We evaluated the complete coding and splice site regions of BRCA1/2 in 193 sporadic patients. In addition, a de novo mutation was further investigated with ultra deep sequencing and microsatellite marker analysis. In 17 patients (8.8%), a deleterious germline BRCA1/2 mutation was identified. The highest mutation detection ratio (3/7 = 42.9%) was obtained in sporadic patients diagnosed with breast and ovarian cancer after the age of 40. In 21 bilateral breast cancer patients, two mutations were identified (9.5%). Furthermore, 140 sporadic patients with unilateral breast cancer were investigated. Mutations were only identified in patients diagnosed with breast cancer before the age of 40 (12/128 = 9.4% vs. 0/12 with Dx > 40). No mutations were detected in 17 sporadic male breast cancer and 6 ovarian cancer patients. BRCA1 c.3494_3495delTT was identified in a patient diagnosed with breast and ovarian cancer at the age of 52 and 53, respectively, and was proven to have occurred de novo at the paternal allele. Our study shows that the mutation detection probability in specific patient subsets can be significant, therefore mutation analysis should be considered in sporadic patients. As a consequence, a family history for the disease and an early age of onset should not be used as the only criteria for mutation analysis of BRCA1/2. The relatively high mutation detection ratio suggests that the prevalence of BRCA1/2 may be underestimated, especially in sporadic patients who developed breast and ovarian cancer. In addition, although rare, the possibility of a de novo occurrence in a sporadic patient should be considered.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Miki Y et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266(5182):66–71

    Article  PubMed  CAS  Google Scholar 

  2. Wooster R et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378(6559):789–792

    Article  PubMed  CAS  Google Scholar 

  3. Wooster R et al (1994) Localization of a breast cancer susceptibility gene, BRCA2, to chromosome 13q12–13. Science 265(5181):2088–2090

    Article  PubMed  CAS  Google Scholar 

  4. Kauff ND et al (2002) Incidence of non-founder BRCA1 and BRCA2 mutations in high risk Ashkenazi breast and ovarian cancer families. J Med Genet 39(8):611–614

    Article  PubMed  CAS  Google Scholar 

  5. Gayther SA et al (1997) Variation of risks of breast and ovarian cancer associated with different germline mutations of the BRCA2 gene. Nat Genet 15(1):103–105

    Article  PubMed  CAS  Google Scholar 

  6. Tesoriero A et al (1999) De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. Am J Hum Genet 65(2):567–569

    Article  PubMed  CAS  Google Scholar 

  7. Edwards E et al (2009) Identification of a de novo BRCA1 mutation in a woman with early onset bilateral breast cancer. Fam Cancer 8(4):479–482

    Article  PubMed  CAS  Google Scholar 

  8. Diez O et al (2010) A novel de novo BRCA2 mutation of paternal origin identified in a Spanish woman with early onset bilateral breast cancer. Breast Cancer Res Treat 121(1):221–225

    Article  PubMed  CAS  Google Scholar 

  9. Hansen TV et al (2008) Novel de novo BRCA2 mutation in a patient with a family history of breast cancer. BMC Med Genet 9:58

    Article  PubMed  Google Scholar 

  10. Marshall M, Solomon S, Lawrence Wickerham D (2009) Case report: de novo BRCA2 gene mutation in a 35-year-old woman with breast cancer. Clin Genet 76(5):427–430

    Article  PubMed  CAS  Google Scholar 

  11. Robson M et al (2002) Unique de novo mutation of BRCA2 in a woman with early onset breast cancer. J Med Genet 39(2):126–128

    Article  PubMed  CAS  Google Scholar 

  12. van der Luijt RB et al (2001) De novo recurrent germline mutation of the BRCA2 gene in a patient with early onset breast cancer. J Med Genet 38(2):102–105

    Article  PubMed  Google Scholar 

  13. Claes K et al (1999) Mutation analysis of the BRCA1 and BRCA2 genes results in the identification of novel and recurrent mutations in 6/16 flemish families with breast and/or ovarian cancer but not in 12 sporadic patients with early-onset disease. Mutations in brief no. 224. Online. Hum Mutat 13(3):256

    Article  PubMed  CAS  Google Scholar 

  14. van der Hout AH et al (2006) A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2: application in a Dutch cancer clinic setting. Hum Mutat 27(7):654–666

    Article  PubMed  Google Scholar 

  15. De Leeneer K et al (2009) Genotyping of frequent BRCA1/2 SNPs with unlabeled probes: a supplement to HRMCA mutation scanning, allowing the strong reduction of sequencing burden. J Mol Diagn JMD 11(5):415–419

    Article  Google Scholar 

  16. De Leeneer K et al (2008) Rapid and sensitive detection of BRCA1/2 mutations in a diagnostic setting: comparison of two high-resolution melting platforms. Clin Chem 54(6):982–989

    Article  PubMed  Google Scholar 

  17. De Leeneer K et al (2011) Massive parallel amplicon sequencing of the breast cancer genes BRCA1 and BRCA2: opportunities, challenges, and limitations. Hum Mutat 32(3):335–344

    Google Scholar 

  18. Rohlin A et al (2009) Parallel sequencing used in detection of mosaic mutations: comparison with four diagnostic DNA screening techniques. Hum Mutat 30(6):1012–1020

    Article  PubMed  CAS  Google Scholar 

  19. Thomas RK et al (2006) Sensitive mutation detection in heterogeneous cancer specimens by massively parallel picoliter reactor sequencing. Nat Med 12(7):852–855

    Article  PubMed  CAS  Google Scholar 

  20. Carlson KM et al (1994) Parent-of-origin effects in multiple endocrine neoplasia type 2B. Am J Hum Genet 55(6):1076–1082

    PubMed  CAS  Google Scholar 

  21. Schuffenecker I et al (1997) Prevalence and parental origin of de novo RET mutations in multiple endocrine neoplasia type 2A and familial medullary thyroid carcinoma, Le Groupe d’Etude des Tumeurs a Calcitonine. Am J Hum Genet 60(1):233–237

    PubMed  CAS  Google Scholar 

  22. Glaser RL et al (2000) Paternal origin of FGFR2 mutations in sporadic cases of Crouzon syndrome and Pfeiffer syndrome. Am J Hum Genet 66(3):768–777

    Article  PubMed  CAS  Google Scholar 

  23. Lazaro C et al (1996) Sex differences in mutational rate and mutational mechanism in the NF1 gene in neurofibromatosis type 1 patients. Hum Genet 98(6):696–699

    Article  PubMed  CAS  Google Scholar 

  24. Claes K et al (1999) Mutation analysis of the BRCA1 and BRCA2 genes in the Belgian patient population and identification of a Belgian founder mutation BRCA1 IVS5 + 3A > G. Dis Markers 15(1–3):69–73

    PubMed  CAS  Google Scholar 

  25. Claes K et al (2004) BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer 90(6):1244–1251

    Article  PubMed  CAS  Google Scholar 

  26. King MC, Marks JH, Mandell JB (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302(5645):643–646

    Article  PubMed  CAS  Google Scholar 

  27. Meijers-Heijboer EJ et al (2000) Presymptomatic DNA testing and prophylactic surgery in families with a BRCA1 or BRCA2 mutation. Lancet 355(9220):2015–2020

    Article  PubMed  CAS  Google Scholar 

  28. Peto J et al (1999) Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 91(11):943–949

    Article  PubMed  CAS  Google Scholar 

  29. Ford M, Murdoch J (1997) The management of ovarian cancer. Br J Hosp Med 58(11):581–583

    PubMed  CAS  Google Scholar 

  30. Couch FJ et al (1996) BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet 13(1):123–125

    Article  PubMed  CAS  Google Scholar 

  31. Haraldsson K et al (1998) BRCA2 germ-line mutations are frequent in male breast cancer patients without a family history of the disease. Cancer Res 58(7):1367–1371

    PubMed  CAS  Google Scholar 

  32. Johannesdottir G et al (1996) High prevalence of the 999del5 mutation in icelandic breast and ovarian cancer patients. Cancer Res 56(16):3663–3665

    PubMed  CAS  Google Scholar 

  33. Mavraki E et al (1997) Germline BRCA2 mutations in men with breast cancer. Br J Cancer 76(11):1428–1431

    Article  PubMed  CAS  Google Scholar 

  34. Syrjakoski K et al (2004) BRCA2 mutations in 154 Finnish male breast cancer patients. Neoplasia 6(5):541–545

    Article  PubMed  CAS  Google Scholar 

  35. Charef-Hamza S et al (2005) Loss of heterozygosity at the BRCA1 locus in Tunisian women with sporadic breast cancer. Cancer Lett 224(2):185–191

    Article  PubMed  CAS  Google Scholar 

  36. Uhrhammer N et al (2008) BRCA1 mutations in Algerian breast cancer patients: high frequency in young, sporadic cases. Int J Med Sci 5(4):197–202

    Article  PubMed  CAS  Google Scholar 

  37. Ellis D et al (2000) Low prevalence of germline BRCA1 mutations in early onset breast cancer without a family history. J Med Genet 37(10):792–794

    Article  PubMed  CAS  Google Scholar 

  38. Kwon JS et al (2010) Expanding the criteria for BRCA mutation testing in breast cancer survivors. J Clin Oncol 28(27):4214–4220

    Article  PubMed  Google Scholar 

  39. Ottini L et al (2000) BRCA1 and BRCA2 mutations in central and southern Italian patients. Breast Cancer Res BCR 2(4):307–310

    Article  CAS  Google Scholar 

  40. Borg A (2010) Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mut 31(3):E1200-40

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This project was realized with the funding of an Emmanuel van der Schueren scholarship of the Flemish foundation against cancer to Kim De Leeneer. This research was supported by grant 1.5.150.07 from the Fund for Scientific Research Flanders (FWO) to Kathleen Claes and by GOA grant BOF10/GOA/019 (Ghent University). Bruce Poppe is a senior clinical investigator from FWO.

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000, Gent, Belgium

    Kim De Leeneer, Ilse Coene, Brecht Crombez, Justine Simkens, Anne De Paepe, Bruce Poppe & Kathleen Claes

  2. Breast clinic, Department of Gynecology, Ghent University Hospital, Ghent, Belgium

    Rudy Van den Broecke

  3. Breast clinic, Department of Medical Oncology, Heilig Hart Ziekenhuis, Roeselare, Belgium

    Barbara Stragier

  4. Breast clinic, Department of Radiotherapy and Oncology, AZ Sint-Lucas, Gent, Belgium

    Ilse Vanhoutte

  5. Breast clinic, Department of Medical Oncology, AZ Sint-Jan, Brugge, Belgium

    Alain Bols

Authors
  1. Kim De Leeneer
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ilse Coene
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Brecht Crombez
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Justine Simkens
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Rudy Van den Broecke
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alain Bols
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Barbara Stragier
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ilse Vanhoutte
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Anne De Paepe
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Bruce Poppe
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Kathleen Claes
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Kathleen Claes.

Rights and permissions

Reprints and permissions

About this article

Cite this article

De Leeneer, K., Coene, I., Crombez, B. 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 132, 87–95 (2012). https://doi.org/10.1007/s10549-011-1544-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10549-011-1544-9

Keywords

Search

Navigation