Integrated Genome-Wide DNA Copy Number and Expression Analysis Identifies Distinct Mechanisms of Primary Chemoresistance in Ovarian Carcinomas

Abstract

Purpose: A significant number of women with serous ovarian cancer are intrinsically refractory to platinum-based treatment. We analyzed somatic DNA copy number variation and gene expression data to identify key mechanisms associated with primary resistance in advancedstage serous cancers. Experimental Design: Genome-wide copy number variation was measured in 118 ovarian tumors using high-resolution oligonucleotide microarrays. A well-defined subset of 85 advanced-stage serous tumors was then used to relate copy number variation to primary resistance to treatment. The discovery-based approach was complemented by quantitative-PCR copy number analysis of 12 candidate genes as independent validation of previously reported associations with clinical outcome. Likely copy number variation targets and tumor molecular subtypes were further characterized by gene expression profiling. Results: Amplification of 19q12, containing cyclin E (CCNE1), and 20q11.22-q13.12, mapping immediately adjacent to the steroid receptor coactivator NCOA3, was significantly associated with poor response to primary treatment. Other genes previously associated with copy number variation and clinical outcome in ovarian cancer were not associated with primary treatment resistance. Chemoresistant tumors with high CCNE1 copy number and protein expression were associated with increased cellular proliferation but so too was a subset of treatment-responsive patients, suggesting a cell-cycle independent role for CCNE1 in modulating chemoresponse. Patients with a poor clinical outcome without CCNE1 amplification overexpressed genes involved in extracellular matrix deposition. Conclusions: We have identified two distinct mechanisms of primary treatment failure in serous ovarian cancer, involving CCNE1 amplification and enhanced extracellular matrix deposition. CCNE1 copy number is validated as a dominant marker of patient outcome in ovarian cancer.Standard of care for women with advanced-stage ovarian cancer involves primary cytoreductive surgery followed by adjuvant chemotherapy with a platinum-based agent, often regarded as the most active component, and a taxane (1). Although response rates to first-line treatment are high, 20% to 25% of cases relapse during or soon after the cessation of primary therapy (2). The ability to predict treatment response and the development of therapies to counter primary chemoresistance are key goals of ovarian cancer research. Known platinum-resistance mechanisms include reduced drug delivery

Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells

“…Our recent results indicate that Dex could enhance cell adhesion by increasing the expression of some ECM components, such as collagen I and hyaluronic acid, in . This finding is in line with the latest report that the enhanced ECM deposition may play a direct role in primary chemoresistance in ovarian carcinoma (Etemadmoghadam et al 2009). …”

Expression profile of COL2A1 and the pseudogene SLC6A10P predicts tumor recurrence in high‐grade serous ovarian cancer

“…2-7 Several studies on gene profiling of the primary tumor using microarray technology have described potential genes/pathways contributing to chemotherapy resistance and their association with risk stratification/overall survival. [8][9][10][11][12][13][14][15][16][17][18] Unlike the clinical impact of gene profiling on treatment decisions for several solid tumors there has been limited progress with the prediction or the clinical management of recurrent HGSOC.Studies with recurrent ovarian tumors 19 have described surgical and second-line chemotherapy options for the clinical management of the disease. Chromosomal aberrations associated with risk for recurrence have been identified by using comparative genomic hybridization (CGH) analysis.…”

Gene Amplification in Ovarian Carcinomas: Lessons from Selected Amplified Gene Families

“…The association between cyclin E amplification and poor outcome has also been identified in recent German and Japanese studies, although the correlation was not statistically significant in the latter (Mayr et al 2006, Nakayama et al 2010. Two independent labs have also suggested that amplification of the cyclin E gene was associated with primary treatment resistance and targeting cyclin E expression with siRNA reduced cell viability and increased apoptosis (Etemadmoghadam et al 2009, Nakayama et al 2010. These studies suggest that cyclin E amplification/expression may serve as both a prognostic and predictive factor in ovarian cancer as well as a therapeutic target in the treatment of ovarian cancer.…”