gms | German Medical Science

124. Kongress der Deutschen Gesellschaft für Chirurgie

Deutsche Gesellschaft für Chirurgie

01. - 04.05.2007, München

Genome Wide Analysis of Allelic Imbalance in Tumor Epiothelium and Stroma in Patients with BRCA1 and BRCA2 Mutation Positive Hereditary Breast Cancer

Meeting Abstract

  • corresponding author F. Weber - Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
  • A. Frilling - Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
  • L. Shen - Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio, USA
  • K. Sweet - Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio, USA
  • K. Cooper - Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio, USA
  • D. Morrsion - Human Cancer Genetics Program, The Ohio State University, Columbus, Ohio, USA
  • T. Caldes - Laboratory of Molecular Oncology, San Carlos University Hospital, Spain
  • C.E. Broelsch - Klinik für Allgemein-, Viszeral- und Transplantationschirurgie, Universitätsklinikum Essen, Essen, Deutschland
  • C. Eng - Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio, USA

Deutsche Gesellschaft für Chirurgie. 124. Kongress der Deutschen Gesellschaft für Chirurgie. München, 01.-04.05.2007. Düsseldorf: German Medical Science GMS Publishing House; 2007. Doc07dgch7339

Die elektronische Version dieses Artikels ist vollständig und ist verfügbar unter: http://www.egms.de/de/meetings/dgch2007/07dgch075.shtml

Veröffentlicht: 1. Oktober 2007

© 2007 Weber et al.
Dieser Artikel ist ein Open Access-Artikel und steht unter den Creative Commons Lizenzbedingungen (http://creativecommons.org/licenses/by-nc-nd/3.0/deed.de). Er darf vervielf&aauml;ltigt, verbreitet und &oauml;ffentlich zug&aauml;nglich gemacht werden, vorausgesetzt dass Autor und Quelle genannt werden.


Gliederung

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Introduction: We have shown that the tumor microenvironment of of solid tumors is diverse in genetic alterations and contributes to the cancer phenotype. The dynamic morphology of the mammary gland might be of special interest in hereditary breast/ovarian cancer syndrome (HBOC) cases. We hypothesized that hot spots of loss of heterozygosity/allelic imbalance (LOH/AI) within the tumor stroma of BRCA1/2-related breast cancers provide for an impaired mammary stroma that could facilitate later malignant transformation of the breast epithelium.

Materials and methods: We conducted a total genome LOH/AI scan of DNA derived from the epithelium and stroma of 51 BRCA1/2-related breast cancers using 372 microsatellite markers. Compartement specific DNA was obtained by laser capture microdissection.

Results: 19375 informative markers could be evaluated for genomic instability (LOH/AI). BRCA1/2-related breast cancer stroma showed LOH/AI at 59.7% of all loci analyzed, no different than the average frequency of LOH/AI observed in the epithelium (66.2%). Hirachical cluster analysis showed a strong cluster of BRCA1 mutation positive cases. We identified 11 hot spot loci of LOH/AI in the BRCA1/2 stroma, encompassing such genes as POLD1, which functions in DNA replication, and SDHB. We also found for 15 out of 51 subjects the epithelium and stroma group immediately together, 10 of which are BRCA1 mutation positive. Our data indicate that BRCA1/2 deleterious mutation and variants show similar high degree of genomic instability. In addition, the mamary stroma of a BRCA1 mutation positive patient who received prophylactic mastectomy harborded a high significant higher frequency of omic instability than the non-malignant epithelium.

Discussion: The high frequency of LOH manifests the functional effect of BRCA1/2 mutations; disruption of the DNA repair mechanism. The subsequent genetic events can alter the mammary gland architecture as a determining factor for cancer susceptibility. Together, our data indicate that in HBOC breast cancer, the accumulation of genomic instability in the cancer stroma coincides with that of the neoplastic epithelium and we postulate that the stroma might provide for a genetically unstable microenvironment that functions as a landscaper to promote genomic instability in the epithelium and subsequently neoplastic transformation. The disproportional representation of BRCA1 mutation positive cases for which epithelium and stroma cluster directly together lend evidence for an epithelial to mesenchymal transition. Our data underscore the interplay of tumor epithelium and its stroma in the development of hereditary breast cancer.