Molecular profiling of ERBB2-amplified breast cancers

ABSTRACT: 15-25% of breast cancers (BC) show ERBB2-amplification and overexpression of the encoded ERBB2 tyrosine kinase receptor. They are associated with a poor prognosis but can benefit from targeted therapy. A better knowledge of these BCs may help understand their behavior and design new therapeutic strategies. In this study, we defined the high resolution genome and gene expression profiles of 54 ERBB2-amplified BCs using 244K oligonucleotide array-comparative genomic hybridization and whole-genome DNA microarrays. We first identified the ERBB2-C17orf37-GRB7 genomic segment as the minimal common amplicon, and CRKRS and IKZF3 as the most frequent centromeric and telomeric amplicon borders, respectively. Second, we identified 17 genome regions affected by copy number aberration (CNA). The expression of 37 genes of these regions was deregulated. Third, two types of heterogeneity were observed in ERBB2-amplified BCs. The genomic profiles of estrogen receptor-postive (ER+) and negative (ER-) ERBB2-amplified BCs were different. The WNT/Ã?-catenin signaling pathway was involved in ER- ERBB2-amplified BCs, and PVT1 and TRPS1 were candidate oncogenes associated with ER+ ERBB2-amplified BCs. The size of the ERBB2-amplicon was different in inflammatory (IBC) and non inflammatory BCs. ERBB2-amplified IBCs were characterized by the downregulated and upregulated mRNA expression of ten and two genes in proportion to CNA, respectively. We have shown that ERBB2 BCs are heterogeneous and identified genomic features that may be useful in the design of therapeutical strategies Tumor tissues were collected from 340 patients with invasive adenocarcinoma who underwent initial surgery at the Institut Paoli-Calmettes (Marseilles, France) between 1987 and 2007 (from a cohort of 2,175 patients with frozen tumor sample) and from a series of 91 Tunisian T4d tumors (TNM, UICC) treated between 1994 and 1998 at the Salah Azaiz Institute (Tunis, Tunisia). Each patient gave informed consent and the study was approved by our institutional review board. Samples were macrodissected and frozen in liquid nitrogen within 30 minutes of removal. Genomic imbalances were determined by aCGH using 244K CGH oligonucleotide microarrays (Hu-244A, Agilent Technologies). Gene expression data of 51 of the 54 BCs and 4 normal breast (NB) samples (NB1, NB2, NB3 and NB4, representing samples from 4 women and 3 commercial pools of respectively 1, 2 and 4 normal breast RNA, Clontech, Palo Alto, CA) were quantified by using whole-genome DNA microarrays (HG-U133 plus 2.0, Affymetrix).

ORGANISM(S): Homo sapiens

SUBMITTER: Pascal FINETTI 

PROVIDER: E-GEOD-17907 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress