Integrated Cancer Genomics Lab

Current Research

Cancer Genomics to Identify Risk Factors, Disease Genes, and Biomarkers for Ovarian Cancer

Early detection of ovarian cancer is critical to improve the outcomes of patients with ovarian cancer. Unfortunately, currently available biomarkers and screening strategies are inadequte in detecting ovarian cancer at early stage. Consequently, approximately 80% of high-grade serous cancer (the most common subtype of ovarian cancer) is detected at advanced stages. The primary objective of this research focus is to uncover novel disease genes, risk factors, and biomarkers for ovarian cancer. Using high-throughput next-generation sequencing approaches, we are systematically identifying and characterizing risk factors, disease genes, and biomarkers for ovarian cancer. In particular, we are analyzing whole genome sequences of paired normal and tumor genomes from early-stage ovarian cancer. These efforts have led to preliminary identification of candidate genes and regions of interest (ROIs) where high frequency mutations are observed (Figure 1). In addition, we are comprehensively cataloguing all germline sequence variants in these patients with the goal to identify novel ovarian cancer susceptibility genes. We expect that the outcomes of these studies will provide us means to identify women with increased risk for ovarian cancer and to screen for early-stage ovarian cancer in these high-risk women.

Figure 1. Cancer Genomics. To comprehensively characterize somatic mutations in ovarian cancer genomes, we selected 25 ovarian cancer patients, and in collaboration with an industry partner, we have performed whole genome sequencing of 25 pairs of patient-matched normal and cancer genomes. Quality control statistics indicates library insert size of 400 bp with overall average coverage of 40x haploid genomes (left panel). Patient-specific genetic variants were identified by comparing whole genome sequencing data with Human Reference Genome (hg18). Germline variants were subtracted from each corresponding cancer genome to obtain somatic variants. Frequency distributions of somatic mutation per chromosome (right panel) indicate hotspots of somatic mutations in these cancer genomes. This analysis identifies known regions with previously identified cancer genes, GWAS regions with high somatic mutation rates, novel regions containing genes with high frequency mutations, and novel conserved regions with high frequency mutations.

Functional Genomics to Identify Genes and Biological Pathways Regulating Chemotherapy Resistance

Resistance to chemotherapy (either acquired or intrinsic) is a major problem in the successful treatment of ovarian cancer, and it is the main cause of death associated with ovarian cancer. Better understanding of multifactorial nature of chemotherapy resistance in ovarian cancer may provide us effective means to overcome resistance problem. The primary objective of this research focus is to identify and functionally characterize genes and biological pathways that regulate chemotherapy resistance in ovarian cancer. There are two components in this research focus: 1) functional screening of genes that regulate chemotherapy-induced cytotoxicity; and 2) integrative genomics and proteomics to uncover mechanisms of chemotherapy resistance. To identify chemotherapy resistance genes, we are performing genome-wide in vitro screening of cDNA and shRNA libraries and systematically characterizing exogenes and shRNAs that are enriched in resultant resistant clonal cell lines. In addition, we are integrating the microarray gene expression studies and the affinity-based proteomic profiling studies to identify critical genes and biological pathways that are modulating chemotherapy-induced cell death (Figure 2). We expect that the outcomes of these studies will enhance our understanding of chemotherapy resistance in ovarian cancer and may provide us biological basis for targeted therapies to overcome chemotherapy resistance.

Figure 2. Functional Genomics. The primary objective of this research focus is to identify genes and biological pathways regulating chemotherapy resistance in ovarian cancer. The first component of this research focuses on utilizing cell lines, tumor samples, malignant ascites, microarray gene expression studies, and genetic perturbations to identify critical genes and biological pathways (left panel). The second component of research focuses on utilizing cell lines, malignant ascites samples, and affinity-based proteomic profiling to elucidate the role of serine hydroxylases in modulating chemotherapy-induced cytotoxicity (right panel).

Mouse Models with Targeted Fallopian Tubal Carcinogenesis

Although it is generally accepted for many years that epithelial ovarian cancer originates from the surface epithelium of the ovary, an emerging concept suggest that more aggressive high-grade serous cancer may also originate from fimbrial epithelium of the oviduct. The primary objective of this research focus is to generate mouse models for ovarian cancer and to address three fundamental questions in ovarian cancer: 1) Where are the tissues-of-origin for ovarian cancer? 2) What are the characteristics of cancer stem cells? and 3) What are the genetic basis for ovarian carcinogenesis? (Figure 3) To address these fundamental questions, we are currently testing an emerging concept that high-grade serous ovarian cancer may originate from the fallopian tube epithelium. To test this hypothesis, we have generated a mouse model that specifically expresses Cre recombinase in oviductal epithelium (Figure 3). We are using this mouse model to provide answers to three fundamental questions: (a) Can tubal carcinogenesis progress into ovarian cancer? (b) Does it require intact ovaries for carcinogenesis? and (3) What are the minimal genetic alterations that are required to initiate ovarian carcinogenesis? We expect that the outcomes of these studies will improve our understanding of fundamental cancer biology questions associated with tissue-of-origins, the role of cancer stem cells, and the genetic roles of novel tumor suppressors and oncogenes in ovarian carcinogenesis.

Figure 3. Mouse models. The primary objective of this research focus is to provide answers to three fundamental questions in ovarian cancer: namely, the tissue-of-origin, the role of putative cancer stem cells, and critical tumor suppressors and oncogenes (left panel). To accomplish objective, we have generated a mouse model which expressed Cre recombinase in oviductal epithelium. Cre expression was driven by oviduct-specific promoter (right panel, A & B). Using this mouse model, we will address tubal epithelium as point-of-origin for ovarian cancer, the role of putative cancer stem cells (using stem-cell factor driven GFP as a biomarker for cancer stem cells), and the functional role of known and candidate tumor suppressors and oncogenes in ovarian carcinogenesis.