Genomic Analysis Reveals the Molecular Heterogeneity of Ovarian Clear Cell Carcinomas

David S P Tan, Marjan Iravani, W Glenn McCluggage, Maryou B K Lambros, Fernanda Milanezi, Alan Mackay, Charles Gourley, Felipe C Geyer, Radost Vatcheva, Joanne Millar, Karen Thomas, Rachael Natrajan, Kay Savage, Kerry Fenwick, Alistair Williams, Charles Jameson, Mona El-Bahrawy, Martin E Gore, Hani Gabra, Stanley B KayeAlan Ashworth, Jorge S Reis-Filho

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: 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.

Experimental design: 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.

Results: 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.

Conclusions: 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. Clin Cancer Res; 17(6); 1521-34. (C) 2011 AACR.

Original languageEnglish
Pages (from-to)1521-1534
Number of pages14
JournalClinical Cancer Research
Volume17
Issue number6
DOIs
Publication statusPublished - 15 Mar 2011

Cite this