Copy Number Alterations and Transcriptome Profile Analyses Reveal Genetic Determinants Contributing to Higher Paclitaxel-Resistance of Ovarian Clear Cell Adenocarcinoma

Ovarian clear cell adenocarcinoma (OCCA) has been reported to display different characteristics from other histological types of epithelial ovarian cancer. The standard regimen for OCCA therapy includes a platinum agent combined with a taxane, to which the patients frequently acquire resistance which leads to poorer prognosis. Multiple mechanisms have been described for paclitaxel resistance. However, the biological changes in cancer cells while acquiring drug resistance are not fully understood. Genomic instability and copy number alterations in cancer are generally associated with poor prognosis. We sought to identify the copy number alterations (CNAs) and transcriptome profile associated with chemo-resistance of OCCA and the underlying mechanisms. Comparative genomic hybridization (CGH) and RNA sequencing are used to investigate DNA copy number and transcriptome landscapes in OCCA cell line (ES-2) and the selected ES2TR120 and ES2TR300 cells which are shown to be more resistant to paclitaxel. Total 135 and 305 CNAs with gain and loss of copy number, respectively; and 18 up-regulated and 55 down-regulated genes are found in both higher paclitaxel resistant ES2TR cells. Functional annotation and pathway clustering of these candidates reveal that most are related to cell-cell signaling, cell adhesion, cellular movement, cell growth and cycling, as well as metabolic processes. We hereby propose a three-year project to test the hypothesis that long-term exposure to paclitaxel may result in aberrant CNAs and altered gene expression, causing cytoskeleton rearrangement, abnormal cell-cell signaling, cell adhesion and migration, even epithelial-mesenchymal transition (EMT) transformation, thus alter drug-induced stress responses including apoptosis, autophagy or even senescence, allowing a subset of cancer cells surviving from paclitaxel cytotoxicity and exhibiting paclitaxel-resistant phenotype. Followings are the specific aims to be achieved in this project: Specific Aim 1 (1st and 2nd years): We will validate the association of CNAs and differentially expressed genes involving in cell movement, migration and invasion, cell-cell signaling, and cellular growth, and determine their relevance with the higher paclitaxel resistance of OCCA; Specific Aim 2 (2st year): We will estimate the possibility of correcting the CNAs or revising the abnormal expressed gene to reverse higher paclitaxel-resistance of OCCA; Specific Aim 3 (2st and 3th years): We will reveal the underlying mechanisms to explore how paclitaxel-induced CNAs and genes with differential expression can influence cellular behavior, contributing to the paclitaxel responsiveness of OCCA. The success of this study will help us further elucidate the pathways that underlie resistance and identification of prognostic markers for patients.