Classification of High-Grade Serous Ovarian Carcinoma by Epithelial-to-Mesenchymal Transition Signature and Homologous Recombination Repair Genes.

Min-Hwan Sohn,Hyun Hoon Chung,Maria Lee,Jong-Yeon Shin,Jeong-Sun Seo,Se Ik Kim,Hee Seung Kim,Jae-Weon Kim

doi:10.3390/genes12071103

Abstract

High-grade serous ovarian cancer (HGSOC) is one of the deadliest cancers that can occur in women. This study aimed to investigate the molecular characteristics of HGSOC through integrative analysis of multi-omics data. We used fresh-frozen, chemotherapy-naïve primary ovarian cancer tissues and matched blood samples of HGSOC patients and conducted next-generation whole-exome sequencing (WES) and RNA sequencing (RNA-seq). Genomic and transcriptomic profiles were comprehensively compared between patients with germline BRCA1/2 mutations and others with wild-type BRCA1/2. HGSOC samples initially divided into two groups by the presence of germline BRCA1/2 mutations showed mutually exclusive somatic mutation patterns, yet the implementation of high-dimensional analysis of RNA-seq and application of epithelial-to-mesenchymal (EMT) index onto the HGSOC samples revealed that they can be divided into two subtypes; homologous recombination repair (HRR)-activated type and mesenchymal type. Patients with mesenchymal HGSOC, characterized by the activation of the EMT transcriptional program, low genomic alteration and diverse cell-type compositions, exhibited significantly worse overall survival than did those with HRR-activated HGSOC (p = 0.002). In validation with The Cancer Genome Atlas (TCGA) HGSOC data, patients with a high EMT index (≥the median) showed significantly worse overall survival than did those with a low EMT index (<the median) (p = 0.030). In conclusion, through a comprehensive multi-omics approach towards our HGSOC cohorts, two distinctive types of HGSOC (HRR-activated and mesenchymal) were identified. Our novel EMT index seems to be a potential prognostic biomarker for HGSOC.

Highlights

Ovarian cancer, one of the deadliest gynecologic malignancies, is a global burden with an estimated 313,959 new cases and 207,252 cancer deaths each year [1]
Between the gBRCA1/2mut and gBRCA1/2wt groups, no differences were observed in baseline clinicopathologic characteristics (Table 1)
We investigated the molecular characteristics of High-grade serous ovarian cancer (HGSOC) through an integrative analysis of genomic and transcriptomic data obtained from chemotherapy-naïve primary HGSOC tissues

Summary

Introduction

One of the deadliest gynecologic malignancies, is a global burden with an estimated 313,959 new cases and 207,252 cancer deaths each year [1]. The patients’ BRAC1/2 mutational status is of high interest because several poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors are currently available for the treatment of primary and recurrent HGSOC, based on the phase 3 clinical trials, which have demonstrated the significant survival benefit brought by PARP inhibitors [4,5,6,7,8]. In breast cancer, loss of BRCA1 protein is associated with EMT [12]. Such a relationship has been poorly investigated in ovarian cancer. Broadening the molecular understanding of HGSOC and elucidating the underlying mechanisms for EMT in terms of BRCA1/2 gene alterations is expected to open a new horizon in the treatment of HGSOC [13]

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