Abstract
Background
Considerable interobserver variability exists in diagnosis of ovarian high-grade endometrioid carcinoma (HGEC) and high-grade serous carcinoma (HGSC) due to histopathological similarities. While homologous recombination deficiency (HRD) correlates with drug sensitivity in HGSC, the molecular features of HGEC are unclear.
Methods
Fresh-frozen samples from 15 ovarian HGECs and 274 ovarian HGSCs in the JGOG-TR2 cohort were submitted to targeted DNA sequencing, RNA sequencing, DNA methylation array, and SNP array. We additionally analyzed 555 ovarian HGSCs from TCGA-OV and 287 endometrial high-grade carcinomas from TCGA-UCEC.
Results
Unsupervised clustering using copy number signatures identified four distinct tumor groups (C1, C2, C3 and C4). C1 (n = 41) showed CCNE1 amplification and poor survival. C2 (n = 160) and C3 (n = 59) showed high BRCA1/2 alteration frequency with low and moderate ploidy, respectively. C4 (n = 22) was characterized by favorable outcome, higher HGEC proportion, no BRCA1/2 alteration or CCNE1 amplification, and low levels of HRD score, ploidy, intra-tumoral heterogeneity, cell proliferation rate, and WT1 gene expression. Notably, C4 exhibited a normal endometrium-like DNA methylation profile, thus, defined as “HGEC-type” tumors, which were also identified in TCGA-OV and TCGA-UCEC.
Conclusions
Ovarian “HGEC-type” tumors present a non-HRD status, favorable prognosis, and endometrial differentiation, possibly constituting a subset of clinically diagnosed HGSCs.
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Data availability
Processed data and analysis codes to reproduce the results in this study are available in Supplementary table 4 and 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). Controlled access data for the TCGA cases were obtained through dbGaP (access permission phs000178). Gene expression data for the ICON7 cases were obtained through the European Genome-Phenome Archive (accession number EGAS00001003487).
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Acknowledgements
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. We would like to thank all the JGOG members who participated in the JGOG3025-TR2 study; Drs. Makio Shozu, Hiroyuki Shigeta, Kazuhiro Takehara, Akira Kikuchi, Toyomi Sato, Akinori Oki, Shinya Yoshioka, Shinya Sato, Ryuji Kawaguchi, Hisafumi Okura, Takeshi Iwasa, Shoji Kamiura, Masato Kamitomo, Yoichi Aoki, Nao Suzuki, Yoshio Yoshida, Tadashi Kimura, Daisuke Aoki, Kazuyoshi Kato, Hiroaki Kobayashi, Hidemichi Watari, Etsuko Miyagi, Tsuyoshi Saito, Yoshihito Yokoyama, Tsunekazu Kita, Takashi Matsumoto, Satoshi Nagase, Toshiya Yamamoto, Yukio Hirano, Tomoaki Ikeda, Shiro Suzuki, Keiya Fujimori, Nagamasa Maeda, Naohiko Umesaki, Masatoshi Sugita, and Akira Kouyama.
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ST: data analysis and writing the manuscript; RTH: data analysis and review of the manuscript ; KY: sample collection and data analysis; TB: sample collection and review of the manuscript; MS: sample collection and review of the manuscript; HY: sample collection and review of the manuscript; AO: sample collection and review of the manuscript; HK: sample collection and review of the manuscript; KO: sample collection and data analysis; MM: data analysis and review of the manuscript; TE: sample collection and review of the manuscript; NM: design of this study, data analysis and writing the manuscript.
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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.
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For the JGOG3025 study, i.e., clinical data analysis, frozen tumor tissue collection, target sequencing, and future analyses of tumor tissue, written informed consent was obtained from all patients with approval from the Institutional Review Board at each JGOG participating site prior to the start of the study [7]. The JGOG3025-TR2 study was then conducted with the approval of the Ethics Committee of JGOG and the Institutional Ethics Committee of Kindai University (approval number; 29-167), with opt-out patient consent. This study was performed in accordance with the Declaration of Helsinki.
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Takamatsu, S., Hillman, R.T., Yoshihara, K. et al. Molecular classification of ovarian high-grade serous/endometrioid carcinomas through multi-omics analysis: JGOG3025-TR2 study. Br J Cancer (2024). https://doi.org/10.1038/s41416-024-02837-x
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DOI: https://doi.org/10.1038/s41416-024-02837-x