Multiomic Characterization of High-Grade Serous Ovarian Carcinoma Enables High-Resolution Patient Stratification

Purpose: High-grade serous ovarian carcinoma (HGSOC) is the most common ovarian cancer type; most patients experience disease recurrence that accumulates chemoresistance, leading to treatment failure. Genomic and transcriptomic features have been associated with differential outcome and treatment response. However, the relationship between events at the gene sequence, copy number, and gene-expression levels remains poorly defined. Experimental Design: We perform multiomic characterization of a large HGSOC cohort (n 1/4 362) with detailed clinical annotation to interrogate the relationship between patient subgroups defined by specific molecular events. Results: BRCA2-mutant (BRCA2m) and EMSY-overexpressing cases demonstrated prolonged survival [multivariable hazard ratios (HR) 0.40 and 0.51] and significantly higher first-and second-line chemotherapy response rate. CCNE1-gained (CCNE1g) cases dem-onstrated underrepresentation of FIGO stage IV cases, with shorter survival but no significant difference in treatment response. We demonstrate marked overlap between the TCGA-and Tot-hill-derived subtypes. IMR/C2 cases displayed higher BRCA1/2m frequency (25.5%, 32.5%) and significantly greater immune cell infiltration, whereas PRO/C5 cases had the highest CCNE1g rate (23.9%, 22.2%) and were uniformly low in immune cell infiltration. The survival benefit for cases with aberrations in homologous recombination repair (HRR) genes was apparent across all tran-scriptomic subtypes (HR range, 0.48-0.68). There was significant co-occurrence of RB loss and HRR gene aberrations; RB loss was further associated with favorable survival within HRR-aberrant cases (multivariable HR, 0.50). Conclusions: These data paint a high-resolution picture of the molecular landscape in HGSOC, better defining patients who may benefit most from specific molecular therapeutics and highlighting those for whom novel treatment strategies are needed to improve outcomes.

Automated summary

This study characterized the molecular landscape of HGSOC and identified specific molecular events associated with clinical prognosis and treatment response. The results showed that patients with BRCA2 gene mutations and EMSY gene overexpression had longer survival and higher chemotherapy response rate. Patients with CCNE1 gene gain had lower proportion of stage IV cases and shorter survival, but no significant difference in treatment response.