Identification of ovarian high-grade endometrioid-type tumors through multi-omics analysis: JGOG3025-TR2 study
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Objective
There 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.
Methods
Fresh-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.
Results
Four distinct groups were identified in the JGOG cohort. C1 (n=41) showed CCNE1 amplification and poor survival. C2 (n=160) and C3 (n=59) showed a high frequency of BRCA alterations with moderate and low aneuploidy, respectively. C4 (n=22) was characterized by favorable survival, higher frequency of HGEC, absence of both BRCA alteration and CCNE1 amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, and WT1 gene 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.
Conclusions
Ovarian HGEC-type tumors exhibit non-HRD status, a favorable prognosis, and endometrial differentiation, and may comprise a subset of tumors diagnosed as HGSC.
