Breast Cancer Research and Treatment

, Volume 134, Issue 3, pp 1229–1239

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
Epidemiology

DOI: 10.1007/s10549-012-2050-4

Cite this article as:
Heidemann, S., Fischer, C., Engel, C. et al. Breast Cancer Res Treat (2012) 134: 1229. doi:10.1007/s10549-012-2050-4

Abstract

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.

Keywords

BRCA1BRCA2Double heterozygosityDouble heterozygotesDouble mutationGenetic testing

Abbreviations

GCHBOC

German Consortium for Hereditary Breast and Ovarian Cancer

BRCA

Breast cancer gene

CI

Confidence interval (95 %)

DH

Double heterozygotes

dh

Double heterozygosity

DHPLC

High performance liquid chromatography

MLPA

Multiplex ligation-dependent probe amplification

HGVS

Human Genome Variation Society

BIC

Breast cancer information core

LOH

Loss of heterozygosity

Supplementary material

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

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