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Breast Cancer Research
Published in: Breast Cancer Research 3/2010

Open Access 01-06-2010 | Research article

High-resolution genomic and expression analyses of copy number alterations in HER2-amplified breast cancer

Authors: Johan Staaf, Göran Jönsson, Markus Ringnér, Johan Vallon-Christersson, Dorthe Grabau, Adalgeir Arason, Haukur Gunnarsson, Bjarni A Agnarsson, Per-Olof Malmström, Oskar Th Johannsson, Niklas Loman, Rosa B Barkardottir, Åke Borg

Published in: Breast Cancer Research | Issue 3/2010

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Abstract

Introduction

HER2 gene amplification and protein overexpression (HER2+) define a clinically challenging subgroup of breast cancer with variable prognosis and response to therapy. Although gene expression profiling has identified an ERBB2 molecular subtype of breast cancer, it is clear that HER2+ tumors reside in all molecular subtypes and represent a genomically and biologically heterogeneous group, needed to be further characterized in large sample sets.

Methods

Genome-wide DNA copy number profiling, using bacterial artificial chromosome (BAC) array comparative genomic hybridization (aCGH), and global gene expression profiling were performed on 200 and 87 HER2+ tumors, respectively. Genomic Identification of Significant Targets in Cancer (GISTIC) was used to identify significant copy number alterations (CNAs) in HER2+ tumors, which were related to a set of 554 non-HER2 amplified (HER2-) breast tumors. High-resolution oligonucleotide aCGH was used to delineate the 17q12-q21 region in high detail.

Results

The HER2-amplicon was narrowed to an 85.92 kbp region including the TCAP, PNMT, PERLD1, HER2, C17orf37 and GRB7 genes, and higher HER2 copy numbers indicated worse prognosis. In 31% of HER2+ tumors the amplicon extended to TOP2A, defining a subgroup of HER2+ breast cancer associated with estrogen receptor-positive status and with a trend of better survival than HER2+ breast cancers with deleted (18%) or neutral TOP2A (51%). HER2+ tumors were clearly distinguished from HER2- tumors by the presence of recurrent high-level amplifications and firestorm patterns on chromosome 17q. While there was no significant difference between HER2+ and HER2- tumors regarding the incidence of other recurrent high-level amplifications, differences in the co-amplification pattern were observed, as shown by the almost mutually exclusive occurrence of 8p12, 11q13 and 20q13 amplification in HER2+ tumors. GISTIC analysis identified 117 significant CNAs across all autosomes. Supervised analyses revealed: (1) significant CNAs separating HER2+ tumors stratified by clinical variables, and (2) CNAs separating HER2+ from HER2- tumors.

Conclusions

We have performed a comprehensive survey of CNAs in HER2+ breast tumors, pinpointing significant genomic alterations including both known and potentially novel therapeutic targets. Our analysis sheds further light on the genomically complex and heterogeneous nature of HER2+ tumors in relation to other subgroups of breast cancer.
Appendix
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Metadata
Title
High-resolution genomic and expression analyses of copy number alterations in HER2-amplified breast cancer
Authors
Johan Staaf
Göran Jönsson
Markus Ringnér
Johan Vallon-Christersson
Dorthe Grabau
Adalgeir Arason
Haukur Gunnarsson
Bjarni A Agnarsson
Per-Olof Malmström
Oskar Th Johannsson
Niklas Loman
Rosa B Barkardottir
Åke Borg
Publication date
01-06-2010
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 3/2010
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/bcr2568

Other articles of this Issue 3/2010

Breast Cancer Research 3/2010 Go to the issue

Research article

Breast cancer-specific mutations in CK1ε inhibit Wnt/β-catenin and activate the Wnt/Rac1/JNK and NFAT pathways to decrease cell adhesion and promote cell migration

Research article

Role of thioredoxin reductase 1 and thioredoxin interacting protein in prognosis of breast cancer

Research article

Prospectively measured triiodothyronine levels are positively associated with breast cancer risk in postmenopausal women

Letter

Association between the spread of circulating tumor cells and breast cancer subtypes

Research article

Progesterone reverses the mesenchymal phenotypes of basal phenotype breast cancer cells via a membrane progesterone receptor mediated pathway

Research article

Cyclophosphamide- metabolizing enzyme polymorphisms and survival outcomes after adjuvant chemotherapy for node-positive breast cancer: a retrospective cohort study
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Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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