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.

NM received a research grant from AstraZeneca. NM received lecture fees from AstraZeneca, Takeda Pharmaceutical, Eisai, MSD and Chugai Pharmaceutical, and is an outside director of Takara Bio. TB received lecture fees from AstraZeneca. KY received lecture fees and a research grant from AstraZeneca. There are no other competing interests related to this paper.

This work was supported by AstraZeneca K.K. and Merck Sharp & Dohme Corp as the programme of Externally Sponsored Research (ESR-19-14550) and in part by the Japan Agency for Medical Research and development, AMED under Grant Number JP21tm0124005

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The JGOG3025 study (NCT03159572, UMIN 000026303) was approved by the Ethics Committee of JGOG (Japanese Gynecologic Oncology Group) and the Institutional Review Board at each JGOG participating institution with written informed consent from all patients. The JGOG3025-TR2 study was approved by the Ethics Committee of JGOG and the Institutional Ethics Committee of Kindai University (approval number; 29-167), with opt-out patient consent.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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Processed data and analysis codes to reproduce the results in this study are available in the GitHub project page (https://github.com/shirotak/JGOG_HGEOC). Genomic data of the JGOG3025-TR2 cohort, including RNA-seq, SNP array, and DNA methylation array are available from SRA (PRJNA1092599) and NCBI-GEO (GSE263455). Targeted sequencing data and clinical information are available upon reasonable request to JGOG (info@jgog.gr.jp, https://jgog.gr.jp/en/index.html).

https://github.com/shirotak/JGOG_HGEOC

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE263455