Abstract 6076: Compartment-specific multiomic characterisation of ovarian carcinosarcoma
Authors: Hollis Robert L. , Oswald Ailsa , Stillie Lorna J. , Croy Ian , Churchman Michael , Gourley Charlie , Herrington C. Simon 
Published: April 2023

Background: Ovarian carcinosarcoma (OCS) is the most aggressive ovarian cancer type. Risk of relapse and death is high across all patient groups, including those diagnosed at early stage. OCS is biphasic, comprising both carcinomatous and sarcomatous populations, leading to its historic consideration alongside true sarcomas. However, we now recognize that OCS in fact represent metaplastic carcinomas, with the sarcomatous component having undergone complete epithelial to mesenchymal transition (EMT) from carcinoma. Detailed understanding of shared and compartment-specific OCS biology has the potential to identify therapeutic opportunities to improve patient survival.

Methods: We recently curated the largest pathologically-confirmed OCS cohort to date. Here, we perform compartment-specific profiling of 12 cases by mRNA sequencing, whole exome sequencing, microRNA (miRNA) profiling and quantification of tumor-infiltrating lymphocytes. These data paint a detailed picture of shared and compartment-specific biology between matched carcinomatous and sarcomatous compartments.

Results: The sarcomatous compartments harbored significantly fewer infiltrating CD8+ cells (P=0.006), with a significantly lower CD8+:CD3+ cell ratio compared to the carcinomatous components (P=0.002). In 11 of 12 cases, identical TP53 mutations were identified in both cell populations; the remaining case was TP53 wild-type in both compartments. Paired analysis of mRNA sequencing identified 1477 significantly differentially expressed transcripts at FDR&lt;0.01. The sarcomatous compartments demonstrated significantly higher MAPK activity, as determined by the MPAS transcriptomic score (P=0.042). Principal component analysis and unsupervised hierarchical clustering of miRNA expression grouped samples by compartment (carcinomatous versus sarcomatous), rather than by patient, suggesting global differences in the miRNA landscape. Paired analysis identified 131 significantly differentially expressed miRNAs between the two populations (FDR&lt;0.01). Significantly enriched miRNA gene targets were identified using The MiRNA Enrichment Analysis and Annotation Tool (miEAA), identifying key EMT-associated gene targets, including SIRT1, PRDM16, ZEB1, ZEB2 and TGFB signaling components, among other biological processes.

Conclusions: Carcinomatous and sarcomatous compartments of OCS demonstrate marked differences in transcriptomic profiles, immune engagement and miRNA expression patterns. Identification of shared TP53 mutations between compartments supports the notion that OCS represent metaplastic carcinomas. Shared biological events represent opportunities for targeted interventions that may be efficacious against both cell populations, while compartment-specific biological events allude to mechanisms by which the carcinomatous population undergoes EMT to form the sarcomatous compartment.

Citation Format: Robert L. Hollis, Ailsa Oswald, Lorna J. Stillie, Ian Croy, Michael Churchman, Charlie Gourley, C. Simon Herrington. Compartment-specific multiomic characterisation of ovarian carcinosarcoma. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6076.