Abstract
To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer. Twelve ovarian clear cell carcinoma cell lines were subjected to tiling path microarray comparative genomic hybridization and genome-wide expression profiling analysis. Regions of high-level amplification were defined and genes whose expression levels were determined by copy number and correlated with gene amplification were identified. The effects of inhibition of PPM1D were assessed using short hairpin RNA constructs and a small-molecule inhibitor (CCT007093). The prevalence of PPM1D amplification and mRNA expression was determined using chromogenic in situ hybridization and quantitative real-time reverse transcription-PCR in a cohort of pure ovarian clear cell carcinomas and on an independent series of unselected epithelial ovarian cancers. Array-based comparative genomic hybridization analysis revealed regions of high-level amplification on 1q32, 1q42, 2q11, 3q24-q26, 5p15, 7p21-p22, 11q13.2-q13.4, 11q22, 17q21-q22, 17q23.2, 19q12-q13, and 20q13.2. Thirty-four genes mapping to these regions displayed expression levels that correlated with copy number gains/amplification. PPM1D had significantly higher levels of mRNA expression in ovarian clear cell carcinoma cell lines harboring gains/amplifications of 17q23.2. PPM1D inhibition revealed that PPM1D expression and phosphatase activity are selectively required for the survival of ovarian clear cell carcinoma cell lines with 17q23.2 amplification. PPM1D amplification was significantly associated with ovarian clear cell carcinoma histology (P = 0.0003) and found in 10% of primary ovarian clear cell carcinomas. PPM1D expression levels were significantly correlated with PPM1D gene amplification in primary ovarian clear cell carcinomas. Our data provide strong circumstantial evidence that PPM1D is a potential therapeutic target for a subgroup of ovarian clear cell carcinomas.
Highlights
To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer
By overlaying genome-wide data on gene copy number and expression obtained from the analysis of the largest collection of ovarian clear cell carcinoma cell lines to date, we identified a list of genes that are highly likely amplicon drivers and/or therapeutic targets in ovarian clear cell carcinoma cell lines
We present data from the first integrated genomic and transcriptomic characterization of ovarian clear cell carcinoma cell lines
Summary
To identify therapeutic targets in ovarian clear cell carcinomas, a chemoresistant and aggressive type of ovarian cancer. In the context of therapeutic target discovery, inhibiting proteins whose expression is driven by gene amplification or activating genetic mutations is an effective approach (5 – 7). This concept is best exemplified by the successful use of trastuzumab in the treatment of HER2amplified breast cancer [8]. Using a combination of RNA interference methods and chemical inhibition, we show that PPM1D expression is required for the survival of cancer cells with 17q23.2 amplification Amplification of this region was shown to be associated with PPM1D expression levels in primary ovarian clear cell carcinomas. Our study provides an approach for the identification of therapeutic targets in ovarian clear cell carcinoma and validates PPM1D as a therapeutic target for these aggressive cancers
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