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Molecular Diagnostics

Molecular classification of ovarian high-grade serous/endometrioid carcinomas through multi-omics analysis: JGOG3025-TR2 study

British Journal of Cancer (2024)Cite this article

Subjects

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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Fig. 1: Four tumor subtypes based on CNV signatures in the JGOG3025-TR2 cohort.
Fig. 2: Genome-wide DNA methylation analysis associated with cell differentiation of endometrium and fallopian tubes.
Fig. 3: Analysis in TCGA-OV datasets.
Fig. 4: Analysis in TCGA-UCEC.

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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.

Author information

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Shiro Takamatsu & Masaki Mandai

  2. Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Shiro Takamatsu & R. Tyler Hillman

  3. Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Shiro Takamatsu & R. Tyler Hillman

  4. CPRIT Scholar in Cancer Research, Houston, TX, USA

    R. Tyler Hillman

  5. Department of Obstetrics and Gynecology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan

    Kosuke Yoshihara & Takayuki Enomoto

  6. Department of Obstetrics and Gynecology, Iwate Medical University, Morioka, Japan

    Tsukasa Baba

  7. Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Muneaki Shimada

  8. Department of Obstetrics and Gynecology, Tokai University Graduate School of Medicine, Isehara, Japan

    Hiroshi Yoshida

  9. Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Hiroaki Kajiyama

  10. Division of Integrative Genomics, The University of Tokyo, Tokyo, Japan

    Katsutoshi Oda

  11. Department of Obstetrics and Gynecology, Jikei University School of Medicine, Tokyo, Japan

    Aikou Okamoto

  12. Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka-Sayama, Japan

    Noriomi Matsumura

Authors
  1. Shiro Takamatsu
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  2. R. Tyler Hillman
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  3. Kosuke Yoshihara
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  4. Tsukasa Baba
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  5. Muneaki Shimada
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  6. Hiroshi Yoshida
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  7. Hiroaki Kajiyama
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  8. Katsutoshi Oda
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  9. Masaki Mandai
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  10. Aikou Okamoto
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  11. Takayuki Enomoto
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  12. Noriomi Matsumura
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Contributions

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.

Corresponding author

Correspondence to Noriomi Matsumura.

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Competing interests

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.

Ethics

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

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