Analysis of gene expression signatures identifies prognostic and functionally distinct ovarian clear cell carcinoma subtypes
Journal
EBioMedicine
Journal Volume
50
Pages
203-210
Date Issued
2019
Author(s)
Abstract
Background: Ovarian clear cell carcinoma (OCCC) is a histological subtype of epithelial ovarian cancer (EOC) with distinct pathological, biological, and molecular features. OCCCs are more resistant to conventional treatment regimen of EOC and have the worst stage-adjusted prognosis amongst EOC subtypes. As the OCCC incidence rate in Asian populations has significantly increased in recent decades, it is critical to elucidate its molecular features that could lead to OCCC-tailored therapeutic strategies. Methods: Gene expression profiles of 222 OCCC were analyzed by hierarchical clustering and statistical analyses. Findings: We identified two OCCC gene expression subtypes: EpiCC—epithelial-like, which is associated with early-stage disease, with a relatively higher rate of gene mutations in the SWI/SNF complex; and MesCC—mesenchymal-like, associated with late-stage and higher enrichment of immune-related pathway activity. Genetic, copy number and transcriptomic analyses showed that both EpiCC and MesCC carried OCCC-associated aberrations. The EpiCC/MesCC classification was reproducible in validation cohorts and OCCC cell lines. MesCC tumors had a poorer progression-free survival (PFS) than EpiCC tumors (HR: 3·0, p = 0·0006). Functional assays in cell lines showed that the MesCC subtype was more proliferative and more anoikis-resistant than the EpiCC. By applying the EpiCC/MesCC classification to the TCGA renal clear cell carcinoma cohort, our results indicated interoperability of the subtyping scheme, and revealed preferential drug response of MesCC to bevacizumab. Interpretation: The EpiCC/MesCC classification shows promise for prognostic and therapeutic stratification in OCCC patients and warrants further investigation in the context of OCCC gene expression subtype-tailored treatment strategies. ? 2019 The Author(s)
Subjects
Clear cell; Microarray gene expression; Molecular subtype; Ovarian cancer
Other Subjects
bevacizumab; genomic DNA; transcriptome; tumor marker; adjuvant chemotherapy; anoikis; antiangiogenic therapy; Article; cancer classification; cancer morphology; cancer prognosis; cancer staging; cancer survival; cell proliferation; clear cell carcinoma; clinical outcome; cohort analysis; controlled study; copy number variation; disease association; drug response; early cancer; epithelial ovarian clear cell carcinoma; epithelial ovarian clear cell carcinoma; female; gene expression profiling; gene mutation; genetic analysis; human; human cell; jhoc9 cell line; KOC-7C cell line; koc5c cell line; mesenchymal ovarian clear cell carcinoma; mesenchymal ovarian clear cell carcinoma; mutational analysis; nucleotide sequence; ovarian clear cell carcinoma cell line; ovary carcinoma; overall survival; OVISE cell line; OVTOKO cell line; priority journal; progression free survival; reproducibility; RMG-I cell line; RMG-II cell line; rmg5 cell line; signal transduction; taya cell line; transcriptomics; tumor differentiation; validation study; adenocarcinoma; biology; epithelial mesenchymal transition; gene expression profiling; genetics; immunohistochemistry; Kaplan Meier method; mortality; mutation; ovary tumor; procedures; prognosis; proportional hazards model; tumor cell line; Adenocarcinoma, Clear Cell; Biomarkers, Tumor; Cell Line, Tumor; Computational Biology; Epithelial-Mesenchymal Transition; Female; Gene Expression Profiling; Humans; Immunohistochemistry; Kaplan-Meier Estimate; Mutation; Ovarian Neoplasms; Prognosis; Proportional Hazards Models; Reproducibility of Results; Transcriptome
Publisher
Elsevier B.V.
Type
journal article