Ovarian Cancer: Linking Genomics to New Target Discovery and Molecular Markers — The Way Ahead

Abstract

Epithelial ovarian cancer (EOC) is the 4th leading cause of cancer deaths among USA women and the most common cause of death from gynecologic cancers (1, 2). It arises from ovarian surface epithelial (OSE) cells, and is currently classified by surgical and histological appearance (see Table 1), although the predictive value of this morphologic classification is limited (3). Table 1 Current concepts regarding the molecular pathology of specific histologic forms of epithelial ovarian carcinomaa However, while the exact cell of origin and the reasons underlying morphological differences in ovarian tumors are unclear, the histological differentiation of specific ovarian tumors appears to be due to the expression and activity of homeobox genes that regulate differentiation and proliferation of the Mullerian duct (4). The dismal outcome of EOCs is due to the majority of patients presenting with advanced stage III/IV disease. Despite improved median survival in patients with paclitaxel/carboplatin chemotherapy after surgical debulking, relapse occurs in most patients with advanced disease, and only 20% are alive and disease-free at 5 years. Although current efforts to improve outcomes focus on both earlier diagnosis and the incorporation of additional cytotoxic chemotherapy drugs and novel-targeted therapies into treatment, these efforts have not provided significant improvements in patient outcomes in comparison to paclitaxel/carboplatin therapy alone. The results of the ICON5 trial, for example, demonstrate that adding a third cytotoxic agent (gemcitabine, topotecan, or liposomal doxorubicin) to paclitaxel/carboplatin does not prolong progression-free survival in first-line therapy of EOC (5). Current targeted approaches include utilization of epidermal growth factor receptor (EGFR) family inhibitors, or inhibitors of Kit and platelet-derived growth factor receptor (PDGFR), although EGFR and Kit mutations, associated with targeted therapy responsiveness in other tumor types, are rare in EOC. Like many solid tumors, EOC has a high degree of chromosomal instability, and both total and regional instability are associated with altered patient outcomes (6). Unpublished studies from the Gray group and the Ovarian Cancer SPORE support this contention (personal communication). EOC evolves through the multistep acquisition of genomic and epigenetic aberrations that initially deregulate normal cell growth control, followed by autonomous proliferation, and eventually other “hallmark” features of malignancy (7). Although there are only few “hallmarks”, many genomic aberrations contribute to the underlying process, and many of these events act in concert to generate the tumorigenic phenotype. Indeed, aberrations in single oncogenes frequently result in senescence or oncogene-induced death. Combined with the evidence for multiple different nonoverlapping defects in cancer cells, this suggests a major degree of complexity. An improved understanding of the underlying genomic aberrations driving EOC, and how they disrupt protein function leading to oncogenesis is greatly needed. Thus, we have advocated a comprehensive characterization of genomic anomalies in EOC as a common first step in studies that attempt to advance our understanding of ovarian oncogenesis and to discover promising new markers and targets for its therapy. The selection of EOC as one of three tumor types for extensive characterization as part of The Cancer Genome Atlas (TCGA) project offers an excellent opportunity to extend our understanding of this disease. Although genomic mutations commonly affect only a limited number of genes in EOC, chromosomal copy number aberrations typically involve relatively large numbers of genes and other innovative techniques are needed in an attempt to determine a more limited list of genes that act as “key drivers” of oncogenesis. Using breast cancer (BC) as an example, the her2/neu oncogene is considered a “key driver” of the her2/neu amplicon on chromosome 17q, although multiple other nearby genes are frequently coamplified with her2/neu. Whether these coamplified genes are “innocent” passengers or act cooperatively, her2/neu remains an unanswered question. Theoretically, genes selected for mutation as well as “key drivers” of chromosomal copy number alterations that play a key role in the oncogenesis process will manifest significant aberrations at the transcription level and/or protein expression/function than other aberrant gene “passengers” at copy number changes. “Key drivers” represent potential markers for early diagnosis and targets for therapy, their identification are critical. Therefore, study of the transcriptional and proteomic effects of genomically aberrant genes in EOC is essential to determine their importance in the oncogenic process and to explore the antitumor efficacy and proteomic effects of therapies designed to specifically target the protein products of these aberrant genes. Alternatively, a systematic down regulation of each gene in an amplicon may expose phenotypic responses in cells where the genes are amplified. However, such approaches may miss critical aberrations with context-dependent effects such as those that manifest only in vivo. Moreover, as there are too many candidates for systematic analysis of all potential drivers at genomic aberrations, we have concentrated our efforts specifically on genomic changes that correlate with patient outcomes. This imperfect filter focuses on genes that are most likely to provide novel targets or molecular markers.