Skip to main content

Advertisement

SpringerLink
Log in

BRCA1 and BRCA2 germline mutational spectrum and evidence for genetic anticipation in Portuguese breast/ovarian cancer families

  • Editorial Notes
  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

We present the first characterisation of the mutational spectrum of the entire coding sequences and exon–intron boundaries of the BRCA1 and BRCA2 genes as well as large BRCA1 rearrangements in Portuguese families with inherited predisposition to breast/ovarian cancer. Of the 100 probands studied, pathogenic mutations were identified in 22 (24.7%) of 89 breast and/or ovarian cancer families with more than one affected member (15 in BRCA1 and seven in BRCA2), but in none of the 11 patients without family history of cancer. One (6.7%) of the BRCA1 mutations is a large deletion involving exons 11–15. Seven pathogenic point mutations are novel: 2088C>T, 2156delinsCC, and 4255_4256delCT in BRCA1 and 4608_4609delTT, 5036delA, 5583_5584insT, and 8923C>T in BRCA2. The novel 2156delinsCC was identified in three probands from different families and probably represents a founder mutation in our population. We also found a previously reported 3450_3453del4 mutation in three unrelated patients. In addition to the 22 pathogenic mutations, we identified 19 missense mutations of uncertain pathogenic significance, three of them (5241G>C in BRCA1 and IVS6+13C>T and 3731T>C in BRCA2) previously undescribed. The percentage of cases with truncating mutations in BRCA1 and BRCA2 was higher in breast/ovarian cancer (37.0%, mostly BRCA1) and male breast cancer (40%, all BRCA2) families than in families with only female breast cancer (17.5%). Interestingly, we found evidence for genetic anticipation regarding age at diagnosis of both breast and ovarian cancer in those families presenting affected members in more than one generation. These findings should be taken into consideration while planning screening and prophylactic measures in families with inherited predisposition to breast and ovarian cancer.

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.

Abbreviations

BIC:

The breast cancer information core

DGGE:

Denaturing gradient gel electrophoresis

MLPA:

Multiplex ligation-dependent probe amplification

References

  1. Newman B, Austin MA, Lee M et al (1988) Inheritance of human breast cancer: evidence for autosomal dominant transmission in high-risk families. Proc Natl Acad Sci USA 85:3044–3048

    Article  CAS  PubMed  Google Scholar 

  2. King MC, Marks JH, Mandell JB for The New York Breast Cancer Study Group (2003) Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643–646

    Google Scholar 

  3. Hendrickson BC, Judkins T, Ward BD et al (2005) Prevalence of five previously reported and recurrent BRCA1 genetic rearrangement mutations in 20,000 patients from hereditary breast/ovarian cancer families. Genes Chromosomes Cancer 43:309–313

    Article  CAS  PubMed  Google Scholar 

  4. Mazoyer S (2005) Genomic rearrangements in the BRCA1 and BRCA2 genes. Hum Mutat 25:415–422

    Article  CAS  PubMed  Google Scholar 

  5. Simard J, Tonin P, Durocher F, et al (1994) Common origins of BRCA1 mutations in Canadian breast and ovarian cancer families. Nat Genet 8:392–398

    Article  CAS  PubMed  Google Scholar 

  6. Thorlacius S, Olafsdottir G, Tryggvadottir L et al (1996) A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13:117–119

    Article  CAS  PubMed  Google Scholar 

  7. Peelen T, van Vliet M, Petrij-Bosch A et al (1997) A high proportion of novel mutations in BRCA1 with strong founder effects among Dutch and Belgian hereditary breast and ovarian cancer families. Am J Hum Genet 60:1041–1049

    CAS  PubMed  Google Scholar 

  8. Díez O, Osorio A, Duran M et al (2003) Analysis of BRCA1 and BRCA2 genes in Spanish breast/ovarian cancer patients: a high proportion of mutations unique to Spain and evidence of founder effects. Hum Mutat 22:301–312

    Article  PubMed  CAS  Google Scholar 

  9. Soares R, Amendoeira I, Monteiro P et al (2000) Análise de mutações no gene BRCA1 em doentes com cancro da mama e/ou ovário em Portugal. Acta Med Port 13:313–321

    Google Scholar 

  10. Duarte F, Cameselle-Teijeiro JF, Soares R et al (2002) Análisis de mutaciones en los genes BRCA1 y BRCA2 en pacientes com cáncer de mama y ovario del norte de Portugal y Galicia. Rev Clin Esp 202:259–263

    CAS  PubMed  Google Scholar 

  11. Parmigiani G, Berry D, Aguilar O (1998) Determining carrier probabilities for breast cancer-susceptibility genes BRCA1 and BRCA2. Am J Hum Genet 62:145–158

    Article  CAS  PubMed  Google Scholar 

  12. Berry DA, Iversen ES Jr, Gudbjartsson DF et al (2002) BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 20:2701–2712

    Article  CAS  PubMed  Google Scholar 

  13. Van der Hout AH, Van den Ouweland MW, Van der Luijt RB et al (2006, in press) A DGGE system for comprehensive mutation screening of BRCA1 and BRCA2. Application in a Dutch cancer clinic setting. Hum Mutat

  14. Sanger F, Nicklen S, Coulson AR (1997) DNA sequencing with chain-terminating inhibitors. Proc Natl Acad Sci USA 74:5463–5467

    Article  Google Scholar 

  15. Euhus DM, Smith KC, Robinson L et al (2002) Pretest prediction of BRCA1 or BRCA2 mutation by risk counselors and the computer model BRCAPRO. J Natl Cancer Inst 94:844–851

    CAS  PubMed  Google Scholar 

  16. Shih HA, Couch FJ, Nathanson KL et al (2002) BRCA1 and BRCA2 mutation frequency in women evaluated in a breast cancer risk evaluation clinic. J Clin Oncol 20:994–999

    Article  CAS  PubMed  Google Scholar 

  17. Claes K, Poppe B, Coene I et al (2004) BRCA1 and BRCA2 germline mutation spectrum and frequencies in Belgian breast/ovarian cancer families. Br J Cancer 90:1244–1251

    Article  CAS  PubMed  Google Scholar 

  18. Neuhausen S, Gilewski T, Norton L et al (1996) Recurrent BRCA2 6174delT mutations in Ashkenazi Jewish women affected by breast cancer. Nat Genet 13:126–128

    Article  CAS  PubMed  Google Scholar 

  19. Petrij-Bosch A, Peelen T, van Vliet M et al (1997) BRCA1 genomic deletions are major founder mutations in Dutch breast cancer patients. Nat Genet 17:341–345

    Article  CAS  PubMed  Google Scholar 

  20. Møller P, Borg A, Heimdal K et al (2001) The BRCA1 syndrome and other inherited breast or breast-ovarian cancers in a Norwegian prospective series. Eur J Cancer 37:1027–1032

    Article  PubMed  Google Scholar 

  21. Vega A, Campos B, Bressac-De-Paillerets B et al (2001) The R71G BRCA1 is a founder Spanish mutation and leads to aberrant splicing of the transcript. Hum Mutat 17:520–521

    Article  CAS  PubMed  Google Scholar 

  22. Montagna M, Dalla Palma M, Menin C et al (2003) Genomic rearrangements account for more than one-third of the BRCA1 mutations in northern Italian breast/ovarian cancer families. Hum Mol Genet 12:1055–1061

    Article  CAS  PubMed  Google Scholar 

  23. Gad S, Caux-Moncoutier V, Pages-Berhouet S et al (2002) Significant contribution of large BRCA1 gene rearrangements in 120 French breast and ovarian cancer families. Oncogene 21:6841–6847

    Article  CAS  PubMed  Google Scholar 

  24. Osorio A, de la Hoya M, Rodriguez-Lopez R et al (2002) Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer. Int J Cancer 99:305–309

    Article  CAS  PubMed  Google Scholar 

  25. Vallon-Christersson J, Cayanan C, Haraldsson K et al (2001) Functional analysis of BRCA1 C-terminal missense mutations identified in breast and ovarian cancer families. Hum Mol Genet 10:353–360

    Article  CAS  PubMed  Google Scholar 

  26. Szabo CI, Wagner LA, Francisco LV et al (1996) Human, canine and murine BRCA1 genes: sequence comparison among species. Hum Mol Genet 5:1289–1298

    Article  CAS  PubMed  Google Scholar 

  27. Westphalen AA, Russell AM, Buser M et al (2005) Evidence for genetic anticipation in hereditary non-polyposis colorectal cancer. Hum Genet 116:461–465

    Article  CAS  PubMed  Google Scholar 

  28. Horwitz M (1997) The genetics of familial leukemia. Leukemia 11:1347–1359

    Article  CAS  PubMed  Google Scholar 

  29. Segel GB, Lichtman MA (2004) Familial (inherited) leukemia, lymphoma, and myeloma: an overview. Blood Cells Mol Dis 32:246–261

    Article  PubMed  Google Scholar 

  30. Dagan E, Gershoni-Baruch R (2002) Anticipation in hereditary breast cancer. Clin Genet 62:147–150

    Article  CAS  PubMed  Google Scholar 

  31. Paterson AD, Kennedy JL, Petronis A (1996) Evidence for genetic anticipation in non-Mendelian diseases. Am J Hum Genet 59:264–268

    CAS  PubMed  Google Scholar 

  32. Hoh J, Heitjan DF, Merette C et al (2001) Ascertainment and anticipation in family studies. Hum Hered 51:23–26

    Article  CAS  PubMed  Google Scholar 

  33. Goldberg JM, Piver MS, Jishi MF et al (1997) Age at onset of ovarian cancer in women with a strong family history of ovarian cancer. Gynecol Oncol 66:3–9

    Article  CAS  PubMed  Google Scholar 

  34. Tryggvadottir L, Sigvaldason H, Olafsdottir GH et al (2006) Population-based study of changing breast cancer risk in Iceland BRCA2 mutation carriers, 1920–2000. J Natl Cancer Inst 98:116–122

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grant no. 209/2001 awarded by the Portuguese Ministry of Health and by Liga Portuguesa contra o Cancro, Núcleo Regional do Norte. We are grateful to Annemieke van der Hout, Robert Hofstra, Annelies ten Berge, Pieter van der Vlies, and Inge Mulder, from the Department of Clinical Genetics, University Hospital, Groningen, The Netherlands, for their help in setting up BRCA1/BRCA2 mutations analysis.

Author information

Authors and Affiliations

  1. Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal

    Ana Peixoto, Natália Salgueiro, Catarina Santos, Graça Varzim, Patrícia Rocha, Maria José Soares, Sérgio Castedo & Manuel R. Teixeira

  2. Departments of Oncology, Portuguese Oncology Institute, Porto, Portugal

    Deolinda Pereira & Helena Rodrigues

  3. Departments of Epidemiology, Portuguese Oncology Institute, Porto, Portugal

    Maria José Bento

  4. Espírito Santo Hospital, Évora, Portugal

    António Fráguas

  5. St. António General Hospital, Porto, Portugal

    Graça Moura

  6. Coimbra University Hospital, Coimbra, Portugal

    Fernando Regateiro

Authors
  1. Ana Peixoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Natália Salgueiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Catarina Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Graça Varzim
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patrícia Rocha
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Maria José Soares
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Deolinda Pereira
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Helena Rodrigues
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Maria José Bento
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. António Fráguas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Graça Moura
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Fernando Regateiro
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Sérgio Castedo
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Manuel R. Teixeira
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Manuel R. Teixeira.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Peixoto, A., Salgueiro, N., Santos, C. et al. BRCA1 and BRCA2 germline mutational spectrum and evidence for genetic anticipation in Portuguese breast/ovarian cancer families. Familial Cancer 5, 379–387 (2006). https://doi.org/10.1007/s10689-006-0009-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-006-0009-5

Keywords

Search

Navigation