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Genome-wide association study of genetic variations associated with treatment failure after intravesical bacillus Calmette–Guérin therapy for non-muscle invasive bladder cancer

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Abstract

Bacillus Calmette–Guérin (BCG) instillation is a key therapy to manage non-muscle invasive bladder cancer (NMIBC). However, intravesical BCG therapy fails in approximately half of the patients, leading to recurrence and progression. We aimed to reveal the genetic variations associated with treatment failure after intravesical BCG therapy for NMIBC. This study included 91 Japanese patients treated with BCG instillation for NMIBC. Genomic DNA was obtained from patient whole-blood samples, and a genome-wide association study and genoty** for target regions were performed. The association between genetic variation and treatment failure was analyzed by genome-wide association in 44 patients as the discovery cohort. As a validation study, candidate single nucleotide polymorphisms (SNPs) were examined among 47 patients in another cohort. The genome-wide association study indicated 19 candidate SNPs (rs1607282, rs7825442, rs1319325, rs3738088, rs4250, rs11894207, rs161448, rs2764326, rs2814707, rs3787194, rs58081719, rs3095966, rs73520681, rs16877113, rs16887173, rs10269584, rs11772249, rs118137814, and rs61094339) associated with BCG failure. Following the cumulative analysis of candidate SNPs, 2-gene (rs73520681 and rs61094339) and 4-gene (rs4250, rs11894207, rs73520681, and rs61094339) models successfully predicted treatment failure after intravesical BCG therapy. This study showed that several SNPs were possibly associated with outcome after intravesical BCG therapy in a Japanese population with NMIBC. The cumulative models of these SNPs may have value in clinical applications, although this should be confirmed in future studies.

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Acknowledgements

We would like to thank Edanz Group Japan for editorial assistance, and Ms. Noriko Hakoda and Ms. Eriko Gunshima for technical assistance. We particularly thank Dr. Atsushi Doi (Cell Innovator, Fukuoka, Japan) for excellent guidance in GWAS statistical analysis.

Funding

This work was supported by a Research Grant from Suzuki Urological Research Foundation, which did not play any role in this study.

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Author notes

  1. Masaki Shiota, Naohiro Fujimoto, and Yoshiaki Yamamoto have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Masaki Shiota, Ario Takeuchi, Katsunori Tatsugami & Masatoshi Eto

  2. Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807-8556, Japan

    Naohiro Fujimoto

  3. Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, 755-8505, Japan

    Yoshiaki Yamamoto & Hideyasu Matsuyama

  4. Department of Clinical Chemistry and Laboratory Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

    Takeshi Uchiumi

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Contributions

MS, NF, and YY designed the study. MS carried out the experimental studies, performed the statistical analysis, and drafted the manuscript. All other authors have contributed to data collection and interpretation and critically reviewed the manuscript. MS supervised the study. All authors read and approved the final manuscript.

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Correspondence to Masaki Shiota.

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The study was conducted under review board at Kyushu University (727-01).

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Written informed consent was obtained from all patients.

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Shiota, M., Fujimoto, N., Yamamoto, Y. et al. Genome-wide association study of genetic variations associated with treatment failure after intravesical bacillus Calmette–Guérin therapy for non-muscle invasive bladder cancer. Cancer Immunol Immunother 69, 1155–1163 (2020). https://doi.org/10.1007/s00262-020-02533-8

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