Identifying Genes Associated with Chemotherapy Response in Ovarian Carcinomas Based on DNA Copy Number and Expression Profiles Fang-Han Hsu 1 , Erchin Serpedin 1 , Tzu-Hung Hsiao 3 , Alexander J.R. Bishop 3,4 , Edward R. Dougherty 1,2∗ , and Yidong Chen 3,5∗ 1 Department of Electrical and Computer Engineering, Texas A&M University, College Station, TX 2 Computational Biology Division, Translational Genomics Research Institute, Phoenix, AZ 3 Greehey Children’s Cancer Research Institute, 4 Department of Cellular and Structural Biology, 5 Department of Epidemiology and Biostatistics, University of Texas Health Science Center at San Antonio, San Antonio, TX Email: edward@ece.tamu.edu, cheny8@uthscsa.edu Abstract—DNA copy number alterations (CNAs) may change transcription profiles and are reported to be associated with chemotherapy response. Using a recently concluded ovarian cancer study derived from the Cancer Genome Atlas (TCGA) Research Network, we selected 98 ovarian cancer samples derived from patients who were only treated with Paclitaxel/Carboplatin after the surgery. A statistical testing procedure was proposed to examine the genes with CNAs and correlated changes in expression level, and their associated response to chemotherapy in progression-free survival. Among 12,042 genes under consideration, 112 genes with CNAs and correlated gene expression levels were found to be associated with progression-free survival (PFS) significantly. The region con- taining many selected genes, 1p35.1-1p34.2, is closely examined as a candidate segment where CNAs are significantly associated with chemotherapeutic response to Paclitaxel/Carboplatin. Biological processes and molecular functions associated with chemotherapy response were further proposed based on a gene ontology enrichment analysis. I. I NTRODUCTION Ovarian cancer is prevalent in women [1] and is associated with a high mortality rate as it is usually diagnosed at an advanced stage [2]. A standard treatment of advanced ovar- ian cancer involves surgical resection followed by cycles of adjuvant chemotherapy, typically a combination of a taxane- based and platinum-based cytotoxic agent [3]. Understanding chemotherapy response and identifying the underlying mech- anisms causing chemo resistance is crucial for improving pa- tients’ long-term survival and the development of personalized therapy. Paclitaxel/Carboplatin is one of the most common com- binations of first-line treatments of ovarian cancer [4], [5]. The mechanism of action (MOA) of paclitaxel is to stabilize microtubules and as a result induce mitotic arrest and apoptosis [6]. Carboplatin, a platinum compound related to cisplatin, binds with DNA to form intra-strand crosslinks and adducts that inhibits DNA replication and transcription and leads to DNA breaks and miscodings, and eventually p53-dependent apoptosis. Microarrays have been used to find specific genes and molecular functions associated with chemotherapy resistance. For example, Jazaeri et. al. (2005) detected differentially expressed genes among primary chemosensitive, primary chemoresistant, and postchemotherapy tumors using cDNA- based microarrays [7]. Additionally, Hartmann et. al. (2005) applied a supervised learning algorithm and selected 14 genes to predict the relapsed outcome of ovarian cancer patients after Platinum-Paclitaxel chemotherapy [8]. Etemadmoghadam et. al. (2009) further considered chromosomal aberrations and proposed that DNA copy number alterations (CNAs) at genes such as CCNE1 and NCOA3 are associated with chemoresis- tance [9]. While studies based on microarray techniques have revealed candidate genes (or chromosomal regions) that are associated with chemotherapy response, most of the studies suffered from samples derived from patients treated with a di- versity of chemotherapy (i.e., different drugs). Without careful design of case-control groups, reliable results are difficult to achieve. Recently, the Cancer Genome Atlas (TCGA) Research Net- work concluded an ovarian cancer study with thousands of microarray data including matching mRNA expression, DNA copy number, miRNA, SNP, and CpG methylation data from more than 500 ovarian tumor samples [10]. These array data with complete clinical annotation provide us with a base- line sample collection for studying chemotherapy response. In this TCGA study, ovarian cancer patients are subjected to different chemotherapies or combinations of them, such as Avastin, Bevacizumab, Carboplatin, Cisplatin, Cytoxan, Docetaxel, Doxoribicin, Etoposide, Gemcitabine, Navelbine, Paclitaxel, and many others. To restrict the drug-tumor inter- action, we selected 98 ovarian cancer samples treated with a combined adjuvant chemotherapy using Paclitaxel/Carboplatin only. By performing a series of statistical hypothesis testing, 112 genes with CNAs that correlate with altered expression and progression-free survival (PFS) were detected. Our results suggest that CNAs in the region of 1p35.1-1p34.2 form a 2011 IEEE International Workshop on Genomic Signal Processing and Statistics December 4-6, 2011, San Antonio, Texas, USA 978-1-4673-0490-0/11/$26.00 ©2011 IEEE 46