Identification of ovarian high-grade endometrioid-type tumors through multi-omics analysis: JGOG3025-TR2 study

Abstract

AbstractObjectiveThere is considerable interobserver variability in the differential diagnosis between ovarian high-grade endometrioid carcinoma (HGEC) and ovarian high-grade serous carcinoma (HGSC) due to their histopathological similarities. While the association between homologous recombination deficiency (HRD) and platinum sensitivity and PARP inhibitors is well established in HGSC, the molecular characteristics of HGEC remain unclear.MethodsFresh-frozen tissue samples from 15 ovarian HGECs and 274 ovarian HGSCs morphologically diagnosed by central pathology review in the Japanese Gynecological Oncology Group (JGOG) were subjected to targeted DNA sequencing, RNA sequencing, DNA methylation array, and SNP array analysis. Tumors were classified by unsupervised clustering based on copy number variation signatures. External datasets including 555 ovarian HGSCs and 287 endometrial high-grade carcinomas from The Cancer Genome Atlas project (TCGA-OV and TCGA-UCEC) were also analyzed.ResultsFour distinct groups were identified in the JGOG cohort. C1 (n=41) showedCCNE1amplification and poor survival. C2 (n=160) and C3 (n=59) showed a high frequency ofBRCAalterations with moderate and low aneuploidy, respectively. C4 (n=22) was characterized by favorable survival, higher frequency of HGEC, absence of bothBRCAalteration andCCNE1amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, andWT1gene expression. Additionally, C4 exhibited a normal endometrium-like DNA methylation profile and was defined as an “HGEC-type” tumor. The HGEC-type tumors were also identified in TCGA-OV and TCGA-UCEC.ConclusionsOvarian HGEC-type tumors exhibit non-HRD status, a favorable prognosis, and endometrial differentiation, and may comprise a subset of tumors diagnosed as HGSC.