Genomic and phenotypic analysis of BRCA2mutated breast cancers reveals co-occurring changes linked to progressionReportar como inadecuado




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Breast Cancer Research

, 13:R95

First Online: 29 September 2011Received: 25 January 2011Revised: 12 July 2011Accepted: 29 September 2011

Abstract

BackgroundInherited mutations in the BRCA2 gene greatly increase the risk of developing breast cancer. Consistent with an important role for BRCA2 in error-free DNA repair, complex genomic changes are frequently observed in tumors derived from BRCA2 mutation carriers. Here, we explore the impact of DNA copy-number changes in BRCA2 tumors with respect to phenotype and clinical staging of the disease.

MethodsBreast tumors n = 33 derived from BRCA2 999del5 mutation carriers were examined in terms of copy-number changes with high-resolution aCGH array comparative genomic hybridization containing 385 thousand probes about one for each 7 kbp and expression of phenotypic markers on TMAs tissue microarrays. The data were examined with respect to clinical parameters including TNM staging, histologic grade, S phase, and ploidy.

ResultsTumors from BRCA2 carriers of luminal and basal-triple-negative phenotypes TNPs differ with respect to patterns of DNA copy-number changes. The basal-TNP subtype was characterized by lack of pRb RB1 coupled with high-intense expression of p16 CDKN2A gene products. We found increased proportions of Ki-67-positive cells to be significantly associated with loss of the wild-type wt BRCA2 allele in luminal types, whereas BRCA2wt loss was less frequent in BRCA2 tumors displaying basal-TNP phenotypes. Furthermore, we show that deletions at 13q13.1, involving the BRCA2wt allele, represents a part of a larger network of co-occurring genetic changes, including deletions at 6q22.32-q22.33, 11q14.2-q24.1, and gains at 17q24.1. Importantly, copy-number changes at these BRCA2-linked networking regions coincide with those associated with advanced progression, involving the capacity to metastasize to the nodes or more-distant sites at diagnosis.

ConclusionsThe results presented here demonstrate divergent paths of tumor evolution in BRCA2 carriers and that deletion of the wild-type BRCA2 allele, together with co-occurring changes at 6 q, 11 q, and 17 q, are important events in progression toward advanced disease.

AbbreviationsCGHcomparative genomic hybridization

DSBdouble-stranded break

HRhomologous recombination

IHCimmunohistochemistry

LumALuminal-A

LumBLuminal-B

NHEJnonhomologous end joining

SSAsingle-strand annealing

TMAtissue microarrays

TNPtriple-negative phenotype.

Electronic supplementary materialThe online version of this article doi:10.1186-bcr3020 contains supplementary material, which is available to authorized users.

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Autor: Olafur A Stefansson - Jon G Jonasson - Kristrun Olafsdottir - Hordur Bjarnason - Oskar Th Johannsson - Sigridur K Bodvars

Fuente: https://link.springer.com/







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