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Open Access Highly Accessed Research article

Quantification and clinical relevance of gene amplification at chromosome 17q12-q21 in human epidermal growth factor receptor 2-amplified breast cancers

Pierre-Jean Lamy1*, Frédéric Fina2, Caroline Bascoul-Mollevi3, Anne-Claire Laberenne1, Pierre-Marie Martin2, L'Houcine Ouafik24 and William Jacot5

Author Affiliations

1 Laboratoire de Biologie Spécialisée et d'Oncogénétique, Centre Régional de Lutte contre le Cancer Val d'Aurelle-Paul Lamarque, 208, rue des Apothicaires, Montpellier F-34298, France

2 Laboratoire de Transfert d'Oncologie Biologie, Assistance Publique, Hôpitaux de Marseille, Boulevard Pierre Dramard, Marseille F-13916, France

3 Unité de Biostatistique Centre Régional de Lutte contre le Cancer Val d'Aurelle-Paul Lamarque, 208, rue des Apothicaires, Montpellier F-34298, France

4 UMR 911 CRO2: Centre de Recherche en Oncologie biologique et Oncopharmacologie, Boulevard Pierre Dramard, Marseille F-13344, France

5 Service d'Oncologie Médicale, Centre Régional de Lutte contre le Cancer Val d'Aurelle-Paul Lamarque, 208, rue des Apothicaires, Montpellier F-34298, France

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Breast Cancer Research 2011, 13:R15  doi:10.1186/bcr2824

Published: 2 February 2011

Abstract

Introduction

Human epidermal growth factor receptor 2 (HER2)-amplified breast cancers represent a tumor subtype with chromosome 17q rearrangements that lead to frequent gene amplifications. The aim of this study was to quantify the amplification of genes located on chromosome 17q and to analyze the relations between the pattern of gene amplifications and the patients' characteristics and survival.

Methods

Patients with HER2-positive breast tumors (HER2 score of 3+ by immunohistochemistry or positive for HER2 amplification by fluorescence in situ hybridization (FISH)) (n = 86) and with HER2-negative breast tumors (n = 40) (negative controls) were included in this study. Using a quantitative polymerase chain reaction method and DNA extracted from frozen tumor specimens, 11 genes (MED1, STARD3, HER2, GRB7, THRA, RARA, TOP2A, IGFBP4, CCR7, KRT20, KRT19 and GAS), which are localized within Chr17q12-q21 and have a putative role in breast cancer development, were quantified. Relapse-free and overall survival rates were estimated from the date of surgery to the date of the event of interest (recurrence or death) using the Kaplan-Meier method.

Results

Gene amplification was observed only in HER2-positive tumors, and the frequency of amplification decreased with the distance of the gene from HER2. HER2 presented the highest level of amplification. TOP2A was not included in the smallest region of amplification involving HER2. Amplification of RARA, KRT20 and KRT19 was significantly associated with node-positive breast cancer (P = 0.030, P = 0.002 and P = 0.033, respectively). During a median follow-up period of 55 months (range, 6 to 81 months), the subgroup of patients with hormone receptor-negative cancer and without TOP2A amplification showed the worst survival (relapse-free survival: hazard ratio (HR) = 0.29, 95% confidence interval (95% CI), 0.13 to 0.65, P = 0.001; and overall survival: HR = 0.28, 95% CI, 0.10 to 0.76, P = 0.008).

Conclusions

HER2 amplification seems to drive genomic instability along chromosome 17q, leading to different patterns of gene amplification. This study confirms the clinical importance of identifying, among patients with HER2-positive breast tumors, the subgroup of patients with hormone receptor-negative and nonamplified TOP2A cancers as they have the worst prognosis.