Combined cytogenetic, aCGH and gene expression analyses of cisplatin resistant ovarian cancer cells. A. Tsalenko¹, M. Prasad², J. Paderova², C.-H. Lee², P. Marrano², Z. Yakhini¹, A. Ben-Dor¹, J. Squire², M. Barrett¹. 1) Agilent Laboratories, Santa Clara, CA; 2) Ontario Cancer Institute, Princess Margaret Hospital, University of Toronto, Toronto, Canada.
   Chemotherapies are often restricted by the development of acquired resistance. We use a combination of array-based comparative genomic hybridization (aCGH), high resolution cytogenetics 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; GE was measured with Agilent 44k GE arrays. Aberrant intervals were identified using an efficient aberration detection algorithm ADM1 and integrated with spectral karyotyping (SKY) and chromosome-specific m-banding analyses. The majority of differential aberrations were deletions in A2780cis cells associated with down-regulation 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, 2pter-p25.2, Xq12.2-qter, and loss of one copy of chromosome 13 but with focal (<1Mb) duplication at 13q12.12. In addition A2780cis cells had gain of a single copy of 8q11.22-qter. 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 mBAND and their breakpoints mapped to a single gene resolution. A significant enrichment of differentially expressed genes is observed in these regions including chromosomes 1p (p-value 3.5E-07), 13q (p-value 0.003) and 8q (p-value 0). Gene Ontology analysis revealed functional enrichment of down-regulated 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 down-regulated genes on chromosome 13.