Abstract
BackgroundGenomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu) are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer.MethodsHER2 status was determined using the PathVysion® assay. DNA was extracted after laser microdissection from the 181 paraffin-embedded HER2 amplified (n = 39) or HER2 negative (n = 142) tumor specimens with sufficient tumor available to perform molecular analysis. Allelic imbalance (AI) was assessed using a panel of microsatellite markers representing 26 chromosomal regions commonly altered in breast cancer. Student t-tests and partial correlations were used to investigate relationships between genomic instability and HER2 status.ResultsThe frequency of AI was significantly higher (P < 0.005) in HER2 amplified (27%) compared to HER2 negative tumors (19%). Samples with HER2 amplification showed significantly higher levels of AI (P < 0.05) at chromosomes 11q23, 16q22-q24 and 18q21. Partial correlations including ER status and tumor grade supported associations between HER2 status and alterations at 11q13.1, 16q22-q24 and 18q21.ConclusionThe poor prognosis associated with HER2 amplification may be attributed to global genomic instability as cells with high frequencies of chromosomal alterations have been associated with increased cellular proliferation and aggressive behavior. In addition, high levels of DNA damage may render tumor cells refractory to treatment. In addition, specific alterations at chromosomes 11q13, 16q22-q24, and 18q21, all of which have been associated with aggressive tumor behavior, may serve as genetic modifiers to HER2 amplification. These data not only improve our understanding of HER in breast pathogenesis but may allow more accurate risk profiles and better treatment options to be developed.
Highlights
The HER2 (c-erb-B2, HER-2/neu) gene, located on chromosome 17q12, is a member of the epidermal growth factor receptor family with tyrosine kinase activity [1]
We examined levels and patterns of allelic imbalance (AI) in primary breast tumors with and without HER2 gene amplification to 1) examine associations between amplification of the HER2 gene and global genomic instability and 2) identify chromosomal changes commonly observed in HER2 amplified tumors
Of the 39 HER2+ tumors, six were from patients diagnosed with invasive breast cancer prior to 1998, treatment with trastuzumab was not available for these patients
Summary
The HER2 (c-erb-B2, HER-2/neu) gene, located on chromosome 17q12, is a member of the epidermal growth factor receptor family with tyrosine kinase activity [1]. Amplification of the HER2 gene and/or over-expression of the corresponding protein have been detected in 15–25% of human breast cancers and is associated with poor prognosis [2,3]. To develop more effective treatments for patients with HER2+ breast tumors, efforts have focused on the identification of genes that modify clinical response to trastuzumab including cyclin-dependent kinase inhibitor 1B (p27), phosphatase and tensin homolog (PTEN), insulinlike growth factor 1 receptor (IGF1R) and topoisomerase II α (TOP2A) [7,8,9,10,11]. Genomic alterations of the proto-oncogene c-erbB-2 (HER-2/neu) are associated with aggressive behavior and poor prognosis in patients with breast cancer. The variable clinical outcomes seen in patients with similar HER2 status, given similar treatments, suggests that the effects of amplification of HER2 can be influenced by other genetic changes. To assess the broader genomic implications of structural changes at the HER2 locus, we investigated relationships between genomic instability and HER2 status in patients with invasive breast cancer
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