Abstract
Ovarian cancer is the fifth leading cause of cancer death in women. Ovarian cancers display a high degree of complex genetic alterations involving many oncogenes and tumor suppressor genes. Analysis of the association between genetic alterations and clinical endpoints such as survival will lead to improved patient management via genetic stratification of patients into clinically relevant subgroups. In this study, we aim to define subgroups of high-grade serous ovarian carcinomas that differ with respect to prognosis and overall survival. Genome-wide DNA copy number alterations (CNAs) were measured in 72 clinically annotated, high-grade serous tumors using high-resolution oligonucleotide arrays. Two clinically annotated, independent cohorts were used for validation. Unsupervised hierarchical clustering of copy number data derived from the 72 patient cohort resulted in two clusters with significant difference in progression free survival (PFS) and a marginal difference in overall survival (OS). GISTIC analysis of the two clusters identified altered regions unique to each cluster. Supervised clustering of two independent large cohorts of high-grade serous tumors using the classification scheme derived from the two initial clusters validated our results and identified 8 genomic regions that are distinctly different among the subgroups. These 8 regions map to 8p21.3, 8p23.2, 12p12.1, 17p11.2, 17p12, 19q12, 20q11.21 and 20q13.12; and harbor potential oncogenes and tumor suppressor genes that are likely to be involved in the pathogenesis of ovarian carcinoma. We have identified a set of genetic alterations that could be used for stratification of high-grade serous tumors into clinically relevant treatment subgroups.
Highlights
Epithelial ovarian carcinoma represents the fifth leading cause of cancer death among women in the United States [1,2]
Debulking surgery has become the standard treatment for advanced stage ovarian carcinoma; a residual tumor size of greater than 2 cm is associated with a survival of 12–16 months, compared with 40–45 months if the tumor is less than 2 cm [7,8]
Platinum sensitivity defined as a progression free survival of greater than 6 months following the last dose of adjuvant chemotherapy was observed in 42 of 70 (60%) patients, with 12 patients (17%) demonstrating progressive disease despite chemotherapy
Summary
Epithelial ovarian carcinoma represents the fifth leading cause of cancer death among women in the United States [1,2]. While early-stage ovarian cancers are highly curable, over 70% of ovarian cancer patients are diagnosed with the advanced disease with lower cure rates and are associated with significant morbidity and mortality [4]. Over the past decades there have been significant advances in ovarian cancer treatment as a result of improved surgical techniques and chemotherapy regimens through multiple clinical trials [5,6]. Up to 80% of patients with advanced stage disease experience an initial response to chemotherapy but eventually relapse with a median progression free survival of 18 months [9,10,11,12,13]. Identification of prognostic/predictive markers can improve patient management and allow development of molecularly targeted therapeutics
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