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Genetics and Genomics

Prognostic relevance of HRDness gene expression signature in ovarian high-grade serous carcinoma; JGOG3025-TR2 study

British Journal of Cancer volume 128, pages 1095–1104 (2023)Cite this article

Subjects

Abstract

Background

This study aimed to evaluate the homologous recombination repair pathway deficiency (HRD) in ovarian high-grade serous carcinoma (HGSC).

Methods

In the ovarian cancer data from The Cancer Genome Atlas, we identified genes differentially expressed between tumours with and without HRD genomic scars and named these genes “HRDness signature”. We performed SNP array, RNA sequencing, and methylation array analyses on 274 HGSC tumours for which targeted sequencing of 51 genes and clinical data were available to generate JGOG3025-TR2 dataset. The HRDness signature was tested on external datasets, including the JGOG3025-TR2 cohort, by computational scoring and machine-learning prediction.

Results

High scores and positive predictions of the HRDness signature were significantly associated with BRCA alterations, genomic scar scores, and better survival. On the other hand, among cases with high scores and/or positive predictions, those with BRCA1 methylation showed poorer survival. In the JGOG3025-TR2 cohort, HRD status was significantly associated with the use of olaparib after relapse and progression-free survival after its initiation.

Conclusions

The HRDness gene expression signature is associated with a good prognosis, while BRCA1 methylation is associated with a poor prognosis. The newly generated JGOG3025-TR2 dataset will be useful in future HGSC studies.

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Fig. 1: Analysis of TCGA-OV dataset for genomic scar, survival and HRDness gene expression signature.
Fig. 2: Generation of the JGOG-TR2 dataset and validation of the HRDness signature.
Fig. 3: Prognostic analysis of the JGOG3025-TR2 dataset.
Fig. 4: Survival analysis using the HRDness prediction and the optimised HRD score cut-off in the JGOG-TR2 cohort.
Fig. 5: Survival analysis of the GEO datasets.

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Data availability

The data from SNP array, RNA-seq, DNA methylation array in this study are available from the corresponding authors upon reasonable request. Data sources other than JGOG3025 were summarised in Supplementary Table S7. Controlled access data were obtained through dbGaP access permission (phs000178, phs000892). Data and codes to reproduce the results are available from the corresponding author upon reasonable request.

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Acknowledgements

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.

Funding

This work was supported by AstraZeneca K.K. and Merck Sharp & Dohme Corp as the programme of Externally Sponsored Research (ESR-19-14550).

Author information

Author notes

  1. These authors contributed equally: Shiro Takamatsu, Kosuke Yoshihara.

Authors and Affiliations

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

    Shiro Takamatsu & Masaki Mandai

  2. Department of Obstetrics and Gynecology, Kyoto Okamoto Memorial Hospital, Kyoto, Japan

    Shiro Takamatsu

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

    Kosuke Yoshihara & Takayuki Enomoto

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

    Tsukasa Baba

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

    Muneaki Shimada

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

    Hiroshi Yoshida

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

    Hiroaki Kajiyama

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

    Katsutoshi Oda

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

    Aikou Okamoto

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

    Noriomi Matsumura

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  1. Shiro Takamatsu
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Contributions

ST: data analysis and writing 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: design of this study; NM: data analysis and writing the manuscript.

Corresponding authors

Correspondence to Takayuki Enomoto or Noriomi Matsumura.

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Competing interests

NM received a research grant from AstraZeneca. NM received lecture fees from AstraZeneca and Takeda Pharmaceutical. NM is also 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 approval and consent to participate

For the JGOG3025 study, i.e., clinical data analysis, frozen tumour tissue collection, target sequencing, and future analyses of tumour 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 [16]. 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., Yoshihara, K., Baba, T. et al. Prognostic relevance of HRDness gene expression signature in ovarian high-grade serous carcinoma; JGOG3025-TR2 study. Br J Cancer 128, 1095–1104 (2023). https://doi.org/10.1038/s41416-022-02122-9

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