Molecular Heterogeneity of Endometrioid Ovarian Carcinoma

Abstract

Endometrioid ovarian carcinoma (EOC) has clinical and biological differences compared with other histologic types of ovarian carcinomas, but it shares morphologic and molecular features with endometrioid endometrial carcinoma. To analyze the molecular heterogeneity of EOC according to the new molecular classification of endometrial cancer and to evaluate the prognostic significance of this molecular classification, we have analyzed 166 early-stage EOC by immunohistochemistry for mismatch repair proteins and p53 expression, and by Sanger sequencing for the exonuclease domain of polymerase epsilon (POLE EDM). In addition, we have carried out next-generation sequencing analysis of tumors with POLE EDM mutations to confirm the ultramutated profile. Eight tumors carried POLE EDM mutations and were classified as ultramutated (5%), 29 showed mismatch repair deficiency and were classified as hypermutated (18%), 16 tumors had a mutated pattern of p53 expression and were classified as p53 abnormal (11%), and 114 tumors did not have any of the previous alterations and were classified as no specific type (66%). Five tumors showed >1 classification criteria. The frequencies of ultramutated and hypermutated tumors were lower in EOC compared with the frequency reported in endometrial cancer. Subrogate molecular groups differed in both morphologic features (histologic grade, squamous and morular metaplasia, and necrosis) and immunohistochemical expression of several biomarkers (ARID1A, nuclear β-catenin, estrogen receptors, Napsin A, and HINF1B). In addition, the number of CD8+ tumor-infiltrating lymphocytes was higher in ultramutated and hypermutated tumors. The most commonly mutated genes in the ultramutated group were ARID1A (100%), PIK3R1, PTEN, BCOR, and TP53 (67% each), whereas no mutations were detected in KRAS. Although the prognosis did not differ among subgroups in the multivariate analysis, a trend toward a better prognosis in POLE-mutated and a worse prognosis in p53 abnormal tumors was observed. In addition, this classification could have important therapeutic implications for the use of immunotherapy in tumors classified as ultramutated and hypermutated.

Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

“…By comparison, efforts to apply the endometrial carcinoma molecular classifier—the PROMISE algorithm—have not identified a sizeable proportion of excellent prognosis EnOC patients 20 – 22 ; POLE -mutated tumours are reportedly associated with around 90% 10-year overall patient survival, but account for only 3.5% of cases, limiting implementation of POLE as a prognostic marker. Moreover, two of the four subtypes identified by this algorithm—the MMRd and NSMP groups—account for around 85% of cases and demonstrate equivalent clinical behaviour 21 , limiting the utility of this classification system.…”

“…Though this study did not use routine WT1 IHC to exclude potential HGSOC cases, these data suggest the existence of a true EnOC subgroup with genomic features redolent of HGSOC. Moreover, recent IHC-based studies have identified aberrant p53 expression patterns, indicative of TP53 mutation, in 10–24% of cases 20 – 22 .…”

“…A number of studies have endeavoured to stratify EnOC based on the PROMISE algorithm for endometrial carcinoma classification; however, these have failed to resolve outcome for the majority of EnOC patients with sufficient granularity for clinical implementation, with around 85% of cases classified within the mismatch repair deficient (MMRd) or no specific molecular profile (NSMP) groups which demonstrate equivalent clinical outcome, significantly limiting the utility of PROMISE in EnOC 20 – 22 .…”

A Review of the Clinical Characteristics and Novel Molecular Subtypes of Endometrioid Ovarian Cancer

“…Serous tumor markers such as WT1, P53, CK20, and mucinous tumor markers such as CEA and MUC2 are not often expressed in EOVC and OCCC, and EOVC-specific 2). In addition, tumors of the POLEmut and MMRd groups were less frequent in EOVC compared with those in EC (95,96,101). The distinction in the proportion of molecular classifications also reflects different microenvironments to some extent.…”

“…EOVC patients with TP53 abnormalities had a higher frequency of poorly differentiated cells (G2/G3) ( 95) compared with other molecular types and have the worst prognosis. Research has reported that EOVC with abnormal TP53 may be the result of CTNNB1 mutation (95).…”