Breast Cancer Research and Treatment

, Volume 134, Issue 3, pp 1229–1239 | Cite as

Double heterozygosity for mutations in BRCA1 and BRCA2 in German breast cancer patients: implications on test strategies and clinical management

  • Simone Heidemann
  • Christine Fischer
  • Christoph Engel
  • Barbara Fischer
  • Lana Harder
  • Brigitte Schlegelberger
  • Dieter Niederacher
  • Timm O. Goecke
  • Sandra C. Doelken
  • Nicola Dikow
  • Walter Jonat
  • Susanne Morlot
  • Rita C. Schmutzler
  • Norbert K. Arnold


Double heterozygosity for disease-causing BRCA1 and BRCA2 mutations is a very rare condition in most populations. Here we describe genetic and clinical data of eight female double heterozygotes (DH) for BRCA1 and BRCA2 mutations found in a cohort of 8162 German breast/ovarian cancer families and compare it with the data of their single heterozygous relatives and of the index patients of the German Consortium for Hereditary Breast and Ovarian Cancer. Furthermore, we analyze the phenotypic features of these patients with respect to age at onset of first cancer, first breast/ovarian cancer and the number of disease manifestations and compare them to that of published Caucasian female DHs and their single heterozygous female relatives. German DHs were not significantly younger at diagnosis of first breast cancer than the single heterozygous index patients of the German Consortium. However, if the data of our study were pooled with that of the literature, DHs were substantially younger at onset of first cancer (mean age 40.4 years, 95 % CI = 36.6–44.1) than their single heterozygous female relatives (mean age 51.9 years, 95 % CI = 46.8–57.0). The two groups also differed concerning the onset of first breast cancer (mean age 40.6 years, 95 % CI = 36.6–44.5 vs. 52.6, 95 % CI = 47.5–57.6). In addition, DHs had a more severe disease than their female relatives carrying a single BRCA mutation (1.4 vs. 0.6 manifestations per person). In contrast to Ashkenazi Jewish females, Caucasian DH females might develop breast cancer at an earlier age and have a more severe disease than single heterozygous BRCA mutation carriers. Therefore, DHs may benefit from more intensive surveillance programs/follow-up care and prophylactic surgery.


BRCA1 BRCA2 Double heterozygosity Double heterozygotes Double mutation Genetic testing 



German Consortium for Hereditary Breast and Ovarian Cancer


Breast cancer gene


Confidence interval (95 %)


Double heterozygotes


Double heterozygosity


High performance liquid chromatography


Multiplex ligation-dependent probe amplification


Human Genome Variation Society


Breast cancer information core


Loss of heterozygosity



We thank the German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC) for providing genetic data of the German index patients. The establishment of the German Consortium for Hereditary Breast and Ovarian Cancer (GCHBOC) was made possible by various grants of the German Cancer Aid (Grants no. 70-2006; 70-3268; 70-3277). We thank Meike Kreikemeier, Birgit Teegen, and Doris Karow for excellent technical assistance, Renate Hamann and Elke Janne for excellent patient’s care and Manuela Arnold for careful data documentation. Most of all we thank the patients and their families for their cooperation.


This study complies with the current laws of the Federal Republic of Germany.

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10549_2012_2050_MOESM1_ESM.doc (72 kb)
Supplementary material 1 (DOC 72 kb)


  1. 1.
    Miki Y, Swensen J, Shattuck-Eidens P et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71PubMedCrossRefGoogle Scholar
  2. 2.
    Wooster R, Bignel G, Lancaster J, Swift S, Seal S, Mangion J, Collins N (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792PubMedCrossRefGoogle Scholar
  3. 3.
    Ford D, Easton DF, Peto J (1995) Estimates of the gene frequency of BRCA1 and its contribution to breast and ovarian cancer incidence. Am J Hum Genet 57:1457–1462PubMedGoogle Scholar
  4. 4.
    Antoniou AC, Pharoah PDP, McMullan G, Day NE, Stratton MR, Peto J, Ponder BJ, Easton DF (2002) A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86:76–83PubMedCrossRefGoogle Scholar
  5. 5.
    Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA (1999) The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 64:963–970PubMedCrossRefGoogle Scholar
  6. 6.
    Rennert G, Bisland-Naggan S, Bar-Joseph N (2007) Outcome of breast cancer in BRCA mutation carriers in Israel. N Engl J Med 357:115–123PubMedCrossRefGoogle Scholar
  7. 7.
    Lavie O, Narod S, Lejbkowicz F, Dishon S, Goldberg Y, Gemer O, Rennert G (2011) Double heterozygosity in the BRCA1 and BRCA2 genes in the Jewish population. Ann Oncol 22:964–966PubMedCrossRefGoogle Scholar
  8. 8.
    Liede A, Rehal P, Vesprini D, Jack E, Abrahamson J, Narod SA (1998) A breast cancer patient of Scottish descent with germline mutations in BRCA1 and BRCA2. Am J Hum Genet 62:1543–1544PubMedCrossRefGoogle Scholar
  9. 9.
    Loader S, Rowley PT (1998) Deleterious mutations of both BRCA1 and BRCA2 in three siblings. Genet Test 2:75–77PubMedCrossRefGoogle Scholar
  10. 10.
    Tsongalis GJ, Linfert DR, Johnson RC, Ackroyd R, Berman MM, Ricci A Jr (1998) Double heterozygosity for mutations in the BRCA1 and BRCA2 genes in a breast cancer patient. Arch Pathol Lab Med 122:548–550PubMedGoogle Scholar
  11. 11.
    Tesoriero A, Andersen C, Southey M, Somers G, McKay M, Armes J, McCredie M, Giles G, Hopper JL, Venter D (1999) De novo BRCA1 mutation in a patient with breast cancer and an inherited BRCA2 mutation. Am J Hum Genet 65:567–569PubMedCrossRefGoogle Scholar
  12. 12.
    Caldes T, de la Hoya M, Tosar A, Sulleiro S, Godino J, Ibañez D, Martin M, Perez-Segura P, Diaz-Rubio E (2002) A breast cancer family from Spain with germline mutations in both the BRCA1 and BRCA2 genes. J Med Genet 39:e44PubMedCrossRefGoogle Scholar
  13. 13.
    Cortesi L, Turchetti D, Bertoni C, Zanocco-Marani T, Vinceti M, Silvestri C, Federico M, Silingardi V, Ferrari S (2003) Italian Breast Cancer Res Treat 123 family with two independent mutations: 3358t/a in brca1 and 8756dela in brca2 genes. Eur J Hum Genet 11:210–214PubMedCrossRefGoogle Scholar
  14. 14.
    Choi DH, Lee MH, Bale AE, Carter D, Haffty BG (2004) Incidence of BRCA1 and BRCA2 mutations in young Korean breast cancer patients. J Clin Oncol 22:1638–1645PubMedCrossRefGoogle Scholar
  15. 15.
    Choi DH, Lee MH, Haffty BC (2006) Double heterizygotes for non-Caucasian families with mutations in BRCA1 and BRCA2 genes. Breast J 12:216–220PubMedCrossRefGoogle Scholar
  16. 16.
    Claus EB, Petruzella S, Matloff E, Carter D (2005) Prevalence of BRCA1 and BRCA2 mutations in women diagnosed with ductal carcinoma in situ. JAMA 293:964–969PubMedCrossRefGoogle Scholar
  17. 17.
    Leegte B, van der Hout AH, Deffenbaugh AM, Bakker MK, Mulder IM, ten Berge A, Leenders EP, Wesseling J, de Hullu J, Hoogerbrugge N, Ligtenberg MJ, Ardern-Jones A, Bancroft E, Salmon A, Barwell J, Eeles R, Oosterwijk JC (2005) Phenotypic expression of double heterozygosity for BRCA1 and BRCA2 germline mutations. J Med Genet 42:e20PubMedCrossRefGoogle Scholar
  18. 18.
    Musolino A, Naldi N, Michiara M, Bella MA, Zanelli P, Bortesi B, Cappelletti M, Savi M, Neri TM, Ardizzoni A (2005) A breast cancer patient from Italy with germline mutations in both the BRCA1 and BRCA2 genes. Breast Cancer Res Treat 91:203–205PubMedCrossRefGoogle Scholar
  19. 19.
    Smith M, Fawcett S, Sigalas E, Bell R, Devery S, Andrieska N, Winship I (2008) Familial breast cancer: double heterozygosity for BRCA1 and BRCA2 mutations with differing phenotypes. Fam Cancer 7:119–124PubMedCrossRefGoogle Scholar
  20. 20.
    Pilato B, De Summa S, Danza K, Lambo R, Paradiso A, Tommasi S (2010) Maternal and paternal lineage double heterozygosity alteration in familial breast cancer: a first case report. Breast Cancer Res Treat 124:875–878PubMedCrossRefGoogle Scholar
  21. 21.
    Zuradelli M, Peissel B, Manoukian S, Zaffaroni D, Barile M, Pensotti V, Cavallari U, Masci G, Mariette F, Benski AC, Santoro A, Radice P (2010) Four new cases of double heterozygosity for BRCA1 and BRCA2 gene mutations: clinical, pathological, and family characteristics. Breast Cancer Res Treat 124:251–258PubMedCrossRefGoogle Scholar
  22. 22.
    Augustyn AM, Agostino NM, Namey TL, Nair S, Martino MA (2011) Two patients with germlline mutations in both BRCA1 and BRCA2 discovered unintentionally, a case series and discussion of BRCA testing modalities. Breast Cancer Res Treat 129:629–634PubMedCrossRefGoogle Scholar
  23. 23.
    Interdisziplinare S3-Leitlinie für die Diagnostik, Therapie und Nachsorge des Mammakarzinoms (2008)
  24. 24.
    Meindl A for the German Consortium for Hereditary Breast and Ovarian Cancer (2002) Comprehensive analysis of 989 patients with breast or ovarian cancer provides BRCA1 and BCRA2 mutation profiles and frequencies for the German population. Int J Cancer 97(97):472–480CrossRefGoogle Scholar
  25. 25.
    Schouten JP, McElgunn CJ, Waaijer R, Zwijnenburg D, Diepvens F, Pals G (2002) Relative quantification of 40 nucleic acid sequences by multiplex ligation-dependent probe amplification. Nucl Acids Res 30:e57PubMedCrossRefGoogle Scholar
  26. 26.
    Neuhausen SL, Mazoyer S, Friedman L, Stratton M, Offit K, Caligo A, Tomlinson G, Cannon-Albright L, Bishop T, Kelsell D, Solomon E, Weber B, Couch F, Struewing J, Tonin P, Durocher F, Narod S, Skolnick MH, Lenoir G, Serova O, Ponder B, Stoppa-Lyonnet D, Easton D, King MC, Goldgar DE (1996) Haplotype and phenotype analysis of six recurrent BRCA1 mutations in 61 families: results of an international study. Am J Hum Genet 58:271–280PubMedGoogle Scholar
  27. 27.
  28. 28.
    Craddock JM, Flood CR (1970) The distribution of Chi-squared statistic in small contingency tables. Appl Stat 19:173–181CrossRefGoogle Scholar
  29. 29.
    Chen J, Silver DP, Walpita D, Cantor SB, Gazdar AF, Tomlinson G, Couch FJ, Weber BL, Ashley T, Livingston DM, Scully R (1998) Stable interaction between the products of the BRCA1 and BRCA2 tumor suppressor genes in mitotic and meiotic cells. Mol Cell 3:317–328CrossRefGoogle Scholar
  30. 30.
    Liu Y, West SC (2002) Distinct functions of BRCA1 and BRCA2 in double-strand break repair. Breast Cancer Res 4:9–13PubMedCrossRefGoogle Scholar
  31. 31.
    Gershoni-Baruch R, Dagan E, Kepten I, Freid G (1997) Cosegregation of BRCA1 185delAG mutation and BRCA2 6174delT in one single family. Eur J Cancer 33:2283–2284PubMedCrossRefGoogle Scholar
  32. 32.
    Myriad Genetics Laboratories, Inc. Services and Price List. April 2010Google Scholar

Copyright information

© Springer Science+Business Media, LLC. 2012

Authors and Affiliations

  • Simone Heidemann
    • 1
    • 12
  • Christine Fischer
    • 2
  • Christoph Engel
    • 3
  • Barbara Fischer
    • 1
    • 4
  • Lana Harder
    • 1
    • 12
  • Brigitte Schlegelberger
    • 1
    • 5
  • Dieter Niederacher
    • 6
  • Timm O. Goecke
    • 7
  • Sandra C. Doelken
    • 8
  • Nicola Dikow
    • 2
  • Walter Jonat
    • 9
  • Susanne Morlot
    • 10
  • Rita C. Schmutzler
    • 11
  • Norbert K. Arnold
    • 9
  1. 1.Institute of Human Genetics, University Hospital of Schleswig-HolsteinChristian-Albrechts-University of KielKielGermany
  2. 2.Institute of Human GeneticsUniversity of HeidelbergHeidelbergGermany
  3. 3.Institute for Medical Informatics, Statistics and EpidemiologyUniversity of LeipzigLeipzigGermany
  4. 4.Psychiatric Hospital RicklingRicklingGermany
  5. 5.Institute of Molecular PathologyHannover Medical SchoolHannoverGermany
  6. 6.Department of Gynecology and ObstetricsUniversity of DüsseldorfDüsseldorfGermany
  7. 7.Institute of Human GeneticsUniversity of DüsseldorfDüsseldorfGermany
  8. 8.Institute of Medical and Human GeneticsCharite-UniversitätsmedizinBerlinGermany
  9. 9.Department of Gynecology and Obstetrics, University Hospital of Schleswig-Holstein Christian-Albrechts-University of KielKielGermany
  10. 10.MVZ Wagnerstibbe, HumangenetikHannoverGermany
  11. 11.Centre of Familial Breast and Ovarian Cancer, Department of Gynaecology and Obstetrics and Centre for Integrated Oncology (CIO)University Hospital of CologneCologneGermany
  12. 12.Institute of Tumor GeneticsKielGermany

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