Abstract
IntroductionHuman epidermal growth factor receptor 2 (HER2)-amplified breast cancer represents a clinically well-defined subgroup due to availability of targeted treatment. However, HER2-amplified tumors have been shown to be heterogeneous at the genomic level by genome-wide microarray analyses, pointing towards a need of further investigations for identification of recurrent copy number alterations and delineation of patterns of allelic imbalance.MethodsHigh-density whole genome array-based comparative genomic hybridization (aCGH) and single nucleotide polymorphism (SNP) array data from 260 HER2-amplified breast tumors or cell lines, and 346 HER2-negative breast cancers with molecular subtype information were assembled from different repositories. Copy number alteration (CNA), loss-of-heterozygosity (LOH), copy number neutral allelic imbalance (CNN-AI), subclonal CNA and patterns of tumor DNA ploidy were analyzed using bioinformatical methods such as genomic identification of significant targets in cancer (GISTIC) and genome alteration print (GAP). The patterns of tumor ploidy were confirmed in 338 unrelated breast cancers analyzed by DNA flow cytometry with concurrent BAC aCGH and gene expression data.ResultsA core set of 36 genomic regions commonly affected by copy number gain or loss was identified by integrating results with a previous study, together comprising > 400 HER2-amplified tumors. While CNN-AI frequency appeared evenly distributed over chromosomes in HER2-amplified tumors, not targeting specific regions and often < 20% in frequency, the occurrence of LOH was strongly associated with regions of copy number loss. HER2-amplified and HER2-negative tumors stratified by molecular subtypes displayed different patterns of LOH and CNN-AI, with basal-like tumors showing highest frequencies followed by HER2-amplified and luminal B cases. Tumor aneuploidy was strongly associated with increasing levels of LOH, CNN-AI, CNAs and occurrence of subclonal copy number events, irrespective of subtype. Finally, SNP data from individual tumors indicated that genomic amplification in general appears as monoallelic, that is, it preferentially targets one parental chromosome in HER2-amplified tumors.ConclusionsWe have delineated the genomic landscape of CNAs, amplifications, LOH, and CNN-AI in HER2-amplified breast cancer, but also demonstrated a strong association between different types of genomic aberrations and tumor aneuploidy irrespective of molecular subtype.
Highlights
Human epidermal growth factor receptor 2 (HER2)-amplified breast cancer represents a clinically well-defined subgroup due to availability of targeted treatment
Repeated observations of significant Copy number alteration (CNA) and recurrent amplifications in HER2-amplified breast cancer genomic identification of significant targets in cancer (GISTIC) analysis of 218 primary HER2-amplified tumors profiled by high-density single nucleotide polymorphism (SNP) or oligonucleotide array comparative genomic hybridization (aCGH) identified 80 regions (34 gains and 46 losses) distributed across all autosomes (Figure 1A, Additional file 3)
Among the 99 HER2-amplified tumors we found that cases with lower genome alteration print (GAP)-ploidy, with the exception of hypodiploid cases, harbored less loss of heterozygosity (LOH) and CNN-allelic imbalance (AI) events, as well as less CNAs compared to cases with higher GAP-ploidy (Figure 2F)
Summary
Human epidermal growth factor receptor 2 (HER2)-amplified breast cancer represents a clinically well-defined subgroup due to availability of targeted treatment. Not all patients with HER2 + disease benefit from targeted treatment, and some develop treatment resistance over time It has become evident through microarray-based studies that BC with genomic amplification of HER2 (HER2-amplified) constitutes a biologically heterogeneous subgroup of tumors regarding both gene expression patterns and copy number alterations (CNAs) [4,5]. Such genomic profiles have predominantly been obtained from array comparative genomic hybridization (aCGH) [5,6,7], but more recently single nucleotide polymorphism (SNP) microarrays have become increasingly used, allowing simultaneous detection of both CNAs and allelic imbalance (AI) [8,9,10,11]. Data from HER2-amplified tumors were compared to data from other subgroups of BC, shedding light on a complex landscape of genomic alterations in a clinically important disease entity
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