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Genetics and Genomics

Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer

British Journal of Cancer volume 127, pages 1680–1690 (2022)Cite this article

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Abstract

Background

The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial.

Methods

Germline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed.

Results

Forty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15–3.44 and 1.23–4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations.

Conclusions

Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.

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Fig. 1
Fig. 2
Fig. 3: Prognostic value of pathogenic germline variants in HBOC-associated genes in patients treated with hormonal therapy.
Fig. 4: Summary of the genetic and clinical profiles of patients with somatic variants in the 27 analysed genes.

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Data availability

The sequence data of this study can be accessed at the National Bioscience Database Center (NBDC) under accession number JGAS000509. As the current study used archival blood samples, a statement regarding the deposition of genomic data to public repositories was not included in some of the informed consent forms used in this study. Therefore, a public depository of genomic data was not possible considering the Personal Information Protection Law in Japan for some of the samples included in the present study. However, secondary use of genomic and clinical data is allowed under certain conditions. Please contact the corresponding author for details.

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Acknowledgements

We thank Ms. Eriko Komaki at the Department of Urology, Kyoto University for her technical assistance. The super-computing resource was provided by the Human Genome Center, Institute of Medical Science, the University of Tokyo.

Funding

This work was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (grant number 20H03814). SA received research funding from the Takeda Science Foundation to partially support this study.

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Author notes

  1. These authors contributed equally: Hiroko Kimura, Kei Mizuno.

Authors and Affiliations

  1. Department of Urology, Kyoto University Graduate School of Medicine, Kyoto, Japan

    Hiroko Kimura, Kei Mizuno, Takayuki Sumiyoshi, Takayuki Goto, Takashi Kobayashi, Osamu Ogawa & Shusuke Akamatsu

  2. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Masaki Shiota & Masatoshi Eto

  3. Department of Urology, Akita University Graduate School of Medicine, Akita, Japan

    Shintaro Narita & Tomonori Habuchi

  4. Department of Urology, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

    Naoki Terada & Toshiyuki Kamoto

  5. Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyusyu, Japan

    Naohiro Fujimoto

  6. Department of Urology, Japanese Red Cross Otsu Hospital, Otsu, Japan

    Keiji Ogura, Shotaro Hatano & Satoshi Ishitoya

  7. Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Yusuke Iwasaki, Nozomi Hakozaki & Yukihide Momozawa

  8. Laboratory for Cancer Genomics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan

    Hidewaki Nakagawa & Shusuke Akamatsu

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  1. Hiroko Kimura
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Contributions

SA, MS, SN, NT, NF, HN and YM designed the study. HK, KM, YM, and SA wrote the manuscript. YI, NH and YM performed the sequencing and bioinformatics analyses. HK, KM and SA performed the statistical analyses. HK, KM, MS, SN, NT, NF, KO, SH, SI, TS, TG, T Kobayashi, T Kamoto, ME, TH and OO contributed to sample collection and clinical data acquisition. SA and OO acquired funding.

Corresponding author

Correspondence to Shusuke Akamatsu.

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Competing interests

SA received research funding from Astellas Pharma, AstraZeneca, and Tosoh, outside of the submitted work and honoraria from Janssen Pharmaceutical, AstraZeneca, Astellas Pharma, Sanofi, Bayer and Takeda Pharmaceutical. MS received research funding from Daiichi Sankyo Company and honoraria from Janssen Pharmaceutical, AstraZeneca and Astellas Pharma. SN received honoraria from Janssen Pharmaceutical, Bayer, AstraZeneca, Takeda Pharmaceutical, Sanofi, Nippon Shinyaku and Astellas Pharma. NF received funding from Takeda Pharmaceutical and Sanofi and honoraria from Janssen Pharmaceutical, Takeda Pharmaceutical, Astellas Pharma and Nippon Shinyaku. T Kobayashi received funding from AstraZeneca and Chugai Pharmaceutical and honoraria from Janssen Pharma, AstraZeneca, Chugai Pharmaceutical, Bayer, MSD, Sanofi, Takeda, Astellas, Nippon Shinyaku, Nihon Kayaku, Merck and Pfizer. ME received research funding from Sanofi, Bayers, Astellas Pharma, Ono Pharmaceutical and Takeda Pharmaceutical and honoraria from Ono Pharmaceutical, Takeda Pharmaceutical, Novartis, Pfizer, Bristol Myers Squibb, Janssen Pharmaceutical, MSD and Merck. TH received research funding from Takeda Pharmaceutical, Astellas Pharma, Daiichi Sankyo Company, Sanofi and Bayer and honoraria from Janssen Pharmaceutical, Takeda Pharmaceutical, Astellas Pharma, Daiichi Sankyo Company, AstraZeneca, Sanofi and Bayer. OO received research funding from Shimazu, Astellas Pharma, and Chugai Pharmaceutical and honoraria from Sanofi, Nihon Kayaku, MSD, Bayer, Daiichi Sankyo Company, Ono Pharmaceutical, Nippon Shinyaku and Takeda Pharmaceutical.

Ethics approval and consent to participate

The study, which was conducted in accordance with the Declaration of Helsinki, was approved by the ethics committees of RIKEN, Akita University, Kyusyu University, University of Occupational and Environmental Health, Miyazaki University, Kyoto University (approval number G1154), and the Japanese Red Cross Otsu Hospital. All participants at Akita University, Kyusyu University, University of Occupational and Environmental Health, Miyazaki University, and Kyoto University provided written informed consent for the genomic analysis of their blood samples. Regarding the archived biopsy samples obtained from patients at the Japanese Red Cross Otsu Hospital, even though the patients provided informed consent for the use of their material, genomic analysis was not specified in the consent form. Therefore, to prevent patient re-identification, under the guidance of the ethics committee of Kyoto University, all biopsy samples and clinical data were completely anonymized before the study was conducted.

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Kimura, H., Mizuno, K., Shiota, M. et al. Prognostic significance of pathogenic variants in BRCA1, BRCA2, ATM and PALB2 genes in men undergoing hormonal therapy for advanced prostate cancer. Br J Cancer 127, 1680–1690 (2022). https://doi.org/10.1038/s41416-022-01915-2

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