Molecular Characterization of Breast Cancer with High-Resolution Oligonucleotide Comparative Genomic Hybridization Array

Abstract

Purpose: We used high-resolution oligonucleotide comparative genomic hybridization (CGH) arrays and matching gene expression array data to identify dysregulated genes and to classify breast cancers according to gene copy number anomalies. Experimental Design: DNA was extracted from 106 pretreatment fine needle aspirations of stage II-III breast cancers that received preoperative chemotherapy. CGH was done using Agilent Human 4 Â 44K arrays. Gene expression data generated with Affymetrix U133A gene chips was also available on 103 patients. All P values were adjusted for multiple comparisons.Results: The average number of copy number abnormalities in individual tumors was 76 (range 1-318). Eleven and 37 distinct minimal common regions were gained or lost in >20% of samples, respectively. Several potential therapeutic targets were identified, including FGFR1 that showed high-level amplification in10% of cases. Close correlation between DNA copy number and mRNA expression levels was detected. Nonnegative matrix factorization (NMF) clustering of DNA copy number aberrations revealed three distinct molecular classes in this data set. NMF class I was characterized by a high rate of triple-negative cancers (64%) and gains of 6p21. VEGFA, E2F3, and NOTCH4 were also gained in 29% to 34% of triple-negative tumors. A gain of ERBB2 gene was observed in 52% of NMF class II and class III was characterized by a high rate of estrogen receptor^positive tumors (73%) and a low rate of pathologic complete response to preoperative chemotherapy (3%). Conclusion: The present study identified dysregulated genes that could classify breast cancer and may represent novel therapeutic targets for molecular subsets of cancers.

Reappraisal of putative glyoxalase 1-deficient mouse and dicarbonyl stress on embryonic stem cellsin vitro

“…This is supported by observations in malignant melanoma, for example, where GLO1 copy number increase has low prevalence (2%) in early stages and high prevalence (80 -89%) in advanced stages [68,72,73]. Recent studies have found very high prevalence of GLO1 copy number increase also in gastric cancer (33%) [74] and in "triple negative" breast cancer lacking expression of oestrogen and progesterone receptors and epidermal growth factor receptor-2 genes (83%) [75]. These tumour types do not respond well to currently available chemotherapy; such tumours may be sensitive to permeable Glo1 inhibitor chemotherapy when available clinically [47].…”

Molecular profiling of invasive breast cancer by multiplex ligation-dependent probe amplification-based copy number analysis of tumor suppressor and oncogenes

“…19 Therapeutic or prognostic significance of other frequently amplified genes such as cyclin D1 (CCND1) 20 or frequent loss of genes such as E-cadherin (CDH1) is less clear, and comparative genomic hybridization (CGH) studies have pointed to many more genes and chromosomal loci with potentially important copy number changes. [21][22][23] Nevertheless, no single gene copy number seems to completely explain prognosis or response to therapy of individual breast cancer patients. A simultaneous analysis of copy number changes of a variety of genes involved in prognosis and therapy response may thus be very useful for molecular profiling of individual breast cancer patients.…”

Fibroblast growth factor receptors in breast cancer: expression, downstream effects, and possible drug targets

“…Other genome-wide screens analyzing large groups of unselected breast cancer samples also showed that FGFR2 is rarely amplified (Adelaide et al 2007), and others did not find any amplifications or losses of FGFR2 (Andre et al 2009). However, FGFR2 was amplified in 4% of triplenegative breast cancer samples, whereas no amplification was found in other molecular subtypes.…”

“…Several studies have identified amplifications of FGFR1 in breast cancer (Chin et al 2006, Letessier et al 2006, Reis-Filho et al 2006, Elbauomy Elsheikh et al 2007, Marchio et al 2008, Andre et al 2009, Kadota et al 2009, Moelans et al 2010; Table 1). The percentage of FGFR1 amplifications found using different techniques ranges from 7.5 to 17%.…”

“…Furthermore, each study used a different technique to assess the copy number alterations, which can also account for the discrepancies in the results. Microarray expression analyses showed that FGFR1 amplifications were associated with increased FGFR1 RNA expression (Chin et al 2006, Andre et al 2009). Several studies have described that FGFR1 amplifications were not associated with some pathological characteristics ( Table 2).…”