Similar contributions of BRCA1 and BRCA2 germline mutations to early-onset breast cancer in Germany (original) (raw)

European Journal of Human Genetics volume 11, pages 464–467 (2003)Cite this article

Abstract

This study was undertaken to investigate the prevalence of BRCA1 and BRCA2 germline mutations in 91 German patients unselected for family history, who were diagnosed with breast cancer before the age of 41 years. Clinical information and blood samples were obtained from all patients. A comprehensive BRCA1 and BRCA2 mutational analysis was performed using the protein truncation assay and single-strand conformational polymorphism analysis followed by DNA sequencing of variant signals detected by these assays. Five different deleterious germline mutations including four frameshift mutations and one missense mutation were identified, three in BRCA1 (3.3%) and two mutations (2.2%) in BRCA2. Both BRCA2 mutations are novel and might be specific for the German population. An additional BRCA1 missense mutation previously described and classified as an unknown variant was found. This mutation was also detected in two breast cancer patients of family P 328 and not in 140 healthy controls suggesting that it is disease associated. In addition, one common polymorphism and five novel intronic sequence variants with unknown significance were found. Our findings show that mutations in BRCA1 and BRCA2 may contribute similarly to early-onset breast cancer in Germany. Given current constraints on health-care resources, these results support the notion that BRCA1 and BRCA2 mutation screening may have the strongest impact on health-care when targeted to high-risk populations.

Similar content being viewed by others

References

  1. Miki Y, Swensen J, Shattuck-Eidens D et al: A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 1994; 266: 66–71.
    CAS PubMed Google Scholar
  2. Wooster R, Bignell G, Lancaster J et al: Identification of the breast cancer susceptibility gene BRCA2 [published erratum appears in Nature 1996; 379: 749]. Nature 1995; 378: 789–792.
    CAS PubMed Google Scholar
  3. Tavtigian SV, Simard J, Rommens J et al: The complete BRCA2 gene and mutations in chromosome 13q-linked kindreds [see comments]. Nat Genet 1996; 12: 333–337.
    Article CAS PubMed Google Scholar
  4. Ford D, Easton DF, Stratton M et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 1998; 62: 676–689.
    Article CAS PubMed PubMed Central Google Scholar
  5. The Breast Cancer Linkage Consortium: Cancer risks in BRCA2 mutation carriers. J Natl Cancer Inst 1999; 91: 1310–1316.
  6. Jandrig B, Grade K, Seitz S et al: BRCA1 mutations in German breast-cancer families. Int J Cancer 1996; 68: 188–192.
    Article CAS PubMed Google Scholar
  7. Hamann U, Brauch H, Garvin AM, Bastert G, Scott RJ : German family study on hereditary breast and/or ovarian cancer: germline mutation analysis of the BRCA1 gene. Genes Chrom Cancer 1997; 18: 126–132.
    Article CAS PubMed Google Scholar
  8. Hamann U, Haner M, Stosiek U, Bastert G, Scott RJ : Low frequency of BRCA1 germline mutations in 45 German breast/ovarian cancer families. J Med Genet 1997; 34: 884–888.
    Article CAS PubMed PubMed Central Google Scholar
  9. Hamann U, Liu X, Lange S, Ulmer HU, Benner A, Scott RJ : Contribution of BRCA2 germline mutations to hereditary breast/ovarian cancer in Germany. J Med Genet 2002; 39: e12.
    Article CAS PubMed PubMed Central Google Scholar
  10. Meindl A : Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BRCA2 mutation profiles and frequencies for the German population. Int J Cancer 2002; 97: 472–480.
    Article CAS PubMed Google Scholar
  11. Plaschke J, Commer T, Jacobi C, Schackert HK, Chang-Claude J : BRCA2 germline mutations among early onset breast cancer patients unselected for family history of the disease. J Med Genet 2000; 37: e17.
    Article CAS PubMed PubMed Central Google Scholar
  12. The BRCA1 Exon 13 Duplication Screening Group: The exon 13 duplication in the BRCA1 gene is a founder mutation present in geographically diverse populations. Am J Hum Genet 2000; 67: 207–212.
  13. Breast Cancer Information Core (BIC) database [http://www.nhgri.nih.gov/Intramural_research/Lab_transfer/Bic/]. 2002.
  14. Chen KS, Shepel LA, Haag JD, Heil GM, Gould MN : Cloning, genetic mapping and expression studies of the rat Brca1 gene. Carcinogenesis 1996; 17: 1561–1566.
    Article CAS PubMed Google Scholar
  15. Szabo CI, Wagner LA, Francisco LV et al: Human, canine and murine BRCA1 genes: sequence comparison among species. Hum Mol Genet 1996; 5: 1289–1298.
    Article CAS PubMed Google Scholar
  16. Peto J, Collins N, Barfoot R et al: Prevalence of BRCA1 and BRCA2 gene mutations in patients with early-onset breast cancer. J Natl Cancer Inst 1999; 91: 943–949.
    Article CAS PubMed Google Scholar
  17. Anglian Breast Cancer Study Group: Prevalence and penetrance of BRCA1 and BRCA2 mutations in a population-based series of breast cancer cases. Br. J. Cancer 2000; 83: 1301–1308.
  18. Southey MC, Tesoriero AA, Andersen CR et al: BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer. Br J Cancer 1999; 79: 34–39.
    Article CAS PubMed PubMed Central Google Scholar
  19. Krainer M, Silva-Arrieta S, FitzGerald MG et al: Differential contributions of BRCA1 and BRCA2 to early-onset breast cancer. N Engl J Med 1997; 336: 1416–1421.
    Article CAS PubMed Google Scholar
  20. Loman N, Johannsson O, Kristoffersson U, Olsson H, Borg A : Family history of breast and ovarian cancers and BRCA1 and BRCA2 mutations in a population-based series of early-onset breast cancer. J Natl Cancer Inst 2001; 93:1215–1223.
    Article CAS PubMed Google Scholar
  21. Langston AA, Malone KE, Thompson JD, Daling JR, Ostrander EA : BRCA1 mutations in a population-based sample of young women with breast cancer. N Engl J Med 1996; 334: 137–142.
    Article CAS PubMed Google Scholar
  22. Malone KE, Daling JR, Thompson JD, O’Brien CA, Francisco LV, Ostrander EA : BRCA1 mutations and breast cancer in the general population: analyses in women before age 35 years and in women before age 45 years with first-degree family history. JAMA 1998; 279: 922–929.
    Article CAS PubMed Google Scholar
  23. Malone KE, Daling JR, et al: Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer 2000; 88: 1393–1402.
    Article CAS PubMed Google Scholar

Download references

Acknowledgements

We are grateful to all patients for their participation in this study. This study was in part supported by the Tumorzentrum Heidelberg/Mannheim D.10029190. We thank Rodney J Scott for a critical reading of the manuscript and Antje Seidel-Renkert, Michaela Schleicher and Michael Gilbert for expert technical assistance.

Author information

Author notes

  1. Xuan Liu
    Present address: Hospital of the University for Chinese Medicine, Fang Zhuang/Fang Xing Yuan, 100075, Beijing, China
  2. Nikola Bungardt
    Present address: Institut für Rechtsmedizin der Universität Mainz, Am Pulverturm 3, 55131, Mainz, Germany

Authors and Affiliations

  1. Division of Molecular Genome Analysis, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 280, Heidelberg, 69120, Germany
    Ute Hamann, Xuan Liu & Nikola Bungardt
  2. Städtisches Klinikum, Frauenklinik, Moltkestr. 90, Karlsruhe, 76133, Germany
    Hans Ulrich Ulmer
  3. Women's Clinic, University of Heidelberg, Voßstr. 9, Heidelberg, 69115, Germany
    Gunther Bastert
  4. Department of Pathology, University of Heidelberg, Im Neuenheimer Feld 220, Heidelberg, 69120, Germany
    Hans-Peter Sinn

Authors

  1. Ute Hamann
  2. Xuan Liu
  3. Nikola Bungardt
  4. Hans Ulrich Ulmer
  5. Gunther Bastert
  6. Hans-Peter Sinn

Corresponding author

Correspondence toUte Hamann.

Rights and permissions

About this article

Cite this article

Hamann, U., Liu, X., Bungardt, N. et al. Similar contributions of BRCA1 and BRCA2 germline mutations to early-onset breast cancer in Germany.Eur J Hum Genet 11, 464–467 (2003). https://doi.org/10.1038/sj.ejhg.5200988

Download citation

Keywords

This article is cited by