NPJ Precision Oncology | 2021
Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification
Abstract
Endometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR\u2009+\u2009/ER\u2009+\u2009, PR\u2009+\u2009/ER−) cases were predominantly CTNNB1 -mutant (73.2% vs 18.4%, P \u2009<\u20090.001), while PR-low (PR−/ER\u2009+\u2009, PR−/ER−) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P \u2009=\u20090.001), greater genomic complexity ( P \u2009=\u20090.007) and more frequent copy number alterations ( P \u2009=\u20090.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR\u2009=\u20090.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR\u2009=\u20092.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53 -mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1 -mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy.