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Diagnostic Technologies and Molecular and Cellular Profiling: Genomics-Expression Profiling in Tumors and Model Systems

Combined cytogenetic, aCGH and gene expression analysis of cisplatin resistant ovarian cancer cells

Agilent Technologies, Santa Clara, CA and Ontario Cancer Institute, Toronto, ON, Canada

Abstract

A78

Response to chemotherapies is often restricted by the development of resistance subsequent to treatment. We use a combination of array-based comparative genomic hybridization (aCGH), high resolution cytogenetics (SKY and m-banding analysis), and gene expression (GE) to study the genomic basis of such phenotypes. To demonstrate the utility of combined analyses for studying drug resistance we compared the genomic profiles of A2780 ovarian cancer cells and a cisplatin-resistant derivative (A2780cis). Copy number aberrations were detected with Agilent prototype 95k 60mer oligonucleotide CGH arrays while GE was measured with Agilent 44k GE arrays. Aberrant genomic intervals were identified with using an efficient aberration detection algorithm (Lipson et al, JCB 2006), which identifies all intervals with significant deviation of the average log₂ratio of all probes in the interval from the expected baseline. aCGH data was integrated with spectral karyotyping (SKY) and chromosome-specific m-banding analyses. The majority of differential aberrations were deletions in A2780cis cells associated with downregulation of GE relative to parental A2780 cells. These included deletions on 1p22.1-cen with a nested homozygous deletion targeting the SNX7 locus at 1p21.3, 2ptel-p25.2, Xq12.2-qtel, and loss of one copy of chromosome 13 but with focal (<1Mb) duplication at q12.12. In addition A2780cis cells had gain of a single copy of 8q11.22-qtel. Derivative chromosomes in A2780cis cells, including der(8)t(1;8)(p22;p23) and der(X)t(X;1)(q12;q11) that were associated with differential copy number aberrations, were identified by SKY and m-banding and their breakpoints mapped to a single gene resolution. A significant enrichment of differentially expressed genes is observed in these regions including chromosomes 1 (p-value = 3.5E-07), 13 (p-value = 0.003) and 8q (p-value < 1.0E-11). Gene-Ontology analysis revealed functional enrichment of downregulated genes within the 1p interval in the hydrolase activity category (p-value = 6.08E-07), with more specific terms of GTPase activity ( p-value = 5.85E-06) and ATPase activity (p-value = 0.002). Mitosis (p-value = 0.0002) and cell cycle (p-value = 0.003) pathways are overrepresented in differentially downregulated genes on chromosome 13. The combination of high resolution aCGH, gene expression and molecular cytogenetic data enabled a detailed view of intact and derivative chromosomes leading to significant insights into the genomic basis of acquired drug resistant phenotype in this model system.