Classification of high-grade serous ovarian carcinoma by epithelial-to-mesenchymal transition signature and homologous recombination repair genes
Min-Hwan Sohn 1,2,3,†, Se Ik Kim 4, †, Jong-Yeon Shin 2, Hee Seung Kim 4, Hyun Hoon Chung 4, Jae-Weon Kim 4, Maria Lee 4,5,*, and Jeong-Sun Seo 1,2,3,6,*
1 Precision Medicine Center, Seoul National University Bundang Hospital, Seongnam-si 13605, Korea
2 Precision Medicine Institute, Macrogen Inc., Seongnam-si 13605, Korea
3 Department of Biomedical Sciences, Seoul National University Graduate School, Seoul 03080, Korea
4 Department of Obstetrics and Gynecology, Seoul National University College of Medicine, Seoul 03080, Korea
5 Department of Obstetrics and Gynecology, Seoul National University Hospital, Seoul 03080, Korea
6 Gong-wu Genomic Medicine Institute, Seongnam-si, 13605, Korea
*Correspondence: Maria Lee and Jeong-Sun Seo
† These two authors contributed equally as first authors.
Abstract: https://www.mdpi.com/2073-4425/12/7/1103 Full text pdf: https://www.mdpi.com/2073-4425/12/7/1103/pdf)
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 in-tegrative 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 gen-eration whole exome sequencing (WES) and RNA sequencing (RNA-seq). Genomic and tran-scriptomic profiles were comprehensively compared between patients with germline BRCA1/2 mutation and the 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 appli-cation 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 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 high EMT index (≥ the median) showed significantly worse overall survival than did those with low EMT index (< the median) (P=0.030). In conclusion, through comprehensive multi-omics approach onto 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.
The sequence data were submitted to the Sequence Read Archive (https://www.ncbi.nlm.nih.gov/sra) with BioProject Accession Number PRJNA1068328.