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

Abstract

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 = 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 demonstrated underrepresentation of FIGO stage IV cases, with shorter survival but no significant difference in treatment response. We demonstrate marked overlap between the TCGA- and Tothill-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 transcriptomic 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.

Molecular characteristics and clinical behaviour of epithelial ovarian cancers

“…Recent analyses have revealed relationships between these subtypes identified at the transcriptomic level, and events identified through genomic analysis. Specifically, the immunoreactive subtype appear enriched for HGSOC harbouring BRCA1/2 mutations, while those of the proliferative type appear enriched for tumours with CCNE1 gain [88].…”

“…2C) [87]. CCNE1 copy number gain occurs in 14% of cases and is mutually exclusive with BRCA1/2 mutation [87,88]. Less common mutational events in non-BRCA HRR components (e.g.…”

“…Beyond HRR, whole genome sequencing has identified frequent large structural genomic variants in RB1, PTEN and NF1 [86]. While many of these genomic events, with the exception of TP53 mutation, were previously conceptualised to occur mutually exclusively with one another, it has become clear this is not the case [88,92]. In particular, loss of RB appears to significantly co-occur in cases with BRCA1/2 or other HRR gene perturbations [86,88,92] and disruption of NF1 and PTEN do not appear to be mutually exclusive with other events (Fig.…”

“…In particular, loss of RB appears to significantly co-occur in cases with BRCA1/2 or other HRR gene perturbations [86,88,92] and disruption of NF1 and PTEN do not appear to be mutually exclusive with other events (Fig. 2C) [86,88]. Conversely, CCNE1 gain appears largely mutual exclusive with many other recurrent genomic features [88].…”

“…2C) [86,88]. Conversely, CCNE1 gain appears largely mutual exclusive with many other recurrent genomic features [88].…”