Abstract

Ovarian clear cell carcinomas (OCCC) are a drug-resistant and aggressive type of epithelial ovarian cancer. We analyzed the molecular genetic profiles of OCCCs to determine whether distinct genomic subgroups of OCCCs exist. Fifty pure primary OCCCs were subjected to high-resolution microarray-based comparative genomic hybridization (aCGH). Unsupervised hierarchical clustering using Ward's linkage analysis was performed to identify genomic subgroups of OCCCs. Survival analysis was performed using Kaplan-Meier method and log-rank test. Cox-regression analysis was used to identify independent predictors of outcome. Differentially amplified regions between genomic subgroups of OCCCs were identified using a multi-Fisher's exact test. Hierarchical cluster analysis revealed two distinct clusters of OCCCs with different clinical outcomes. Patients from cluster-1 had a significantly shorter median progression-free survival (PFS) than those from cluster-2 (11 vs. 65 months, P = 0.009), although estimates for ovarian cancer-specific survival (OCS) did not reach statistical significance (P = 0.065). In multivariate analysis, suboptimal debulking surgery and genomic cluster were independently prognostic for PFS. Recurrently amplified genomic regions with a significantly higher prevalence in cluster-1 than cluster-2 OCCCs were identified and validated. HER2 gene amplification and protein overexpression was observed in 14% of OCCCs, suggesting that this may constitute a potential therapeutic target for a subgroup of these tumors. OCCCs constitute a heterogeneous disease at the genomic level despite having similar histological features. The pattern of genomic aberrations in subgroups of OCCCs is of clinical significance. We have identified recurrently amplified regions that may harbor potential therapeutic targets for subgroups of OCCCs.

Highlights

  • HER2 gene amplification and protein overexpression was observed in 14% of Ovarian clear cell carcinomas (OCCC), suggesting that this may constitute a potential therapeutic target for a subgroup of these tumors

  • The pattern of genomic aberrations in subgroups of OCCCs is of clinical significance

  • We have identified recurrently amplified regions that may harbor potential therapeutic targets for subgroups of OCCCs

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Summary

Introduction

Associated with a reduced response rate following platinum-based chemotherapy [1,2,3] and a poorer prognosis, especially in advanced stage, in comparison with other histological subtypes of EOC [4,5,6]. The only established independent prognostic indicators of outcome for OCCCs are International Federation of Gynaecology and Obstetrics (FIGO) stage and the extent of residual disease following debulking surgery [3, 6, 7]. Given that the current standard of care in EOC consists of optimal debulking surgery followed by platinum-based chemotherapy, the observed platinum-resistance of OCCCs, in advanced FIGO stage, poses a considerable clinical challenge. The inability to predict outcomes or platinum/ taxane sensitivity in OCCC patients from intrinsic characteristics of the primary tumor results in considerable difficulty for both patients and gynecological www.aacrjournals.org

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