Multiomic characterisation of high grade serous ovarian carcinoma enables high resolution patient stratification

Hollis, R. L. et al. (2022) Multiomic characterisation of high grade serous ovarian carcinoma enables high resolution patient stratification. Clinical Cancer Research, 28(16), pp. 3546-3556. (doi: 10.1158/1078-0432.CCR-22-0368) (PMID:35696721)

Abstract

Purpose: High grade serous ovarian carcinoma (HGSOC) is the most common ovarian cancer type; most patients experience disease recurrence which 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 characterisation 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 HR 0.40 and 0.51) and significantly higher first- and second-line chemotherapy response rate. CCNE1-gained (CCNE1g) cases demonstrated under-representation 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, while 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 favourable 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.

• Item Type: Articles
• Additional Information: RLH was supported by an MRC-funded fellowship (I171113-1019) and received funding from Target Ovarian Cancer (Edinburgh-CG19), Tenovus Scotland (E19-11) and The Nicola Murray Foundation during the course of this work. AMM and CAS received core funding from the UK Medical Research Council to the MRC Human Genetics Unit (MC_UU_00007/16). COM received funding from The Melville Trust for Care and Cure of Cancer. Sample collection was supported by Cancer Research UK Experimental Cancer Medicine Centre funding. TR was supported by core funding from CRUK awarded to the CRUK Edinburgh Centre. The genomic characterisation of this cohort was funded by a research grant from AstraZeneca.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Roxburgh, Dr Patricia

Creator Roles

Roxburgh, P.: Conceptualization, Supervision, Writing – review and editing

• Authors: Hollis, R. L., Meynert, A. M., Michie, C. O., Rye, T., Churchman, M., Hallas-Potts, A., Croy, I., McCluggage, W. G., Williams, A. R. W., Bartos, C., Iida, Y., Okamoto, A., Dougherty, B., Barrett, J. C., March, R., Matakidou, A., Roxburgh, P., Semple, C. A., Harkin, D. P., Kennedy, R., Herrington, C. S., and Gourley, C.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Clinical Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 1078-0432
• ISSN (Online): 1557-3265
• Published Online: 13 June 2022
• Copyright Holders: Copyright © 2022 American Association for Cancer Research
• First Published: First published in Clinical Cancer Research 28(16): 3546-3556
• Publisher Policy: Reproduced under a Creative Commons license