<scp>GWAS</scp> Identifies <scp>SNPs</scp> Associated With Severe Adverse Events and Efficacy in Advanced Renal Cell Carcinoma Treated With Nivolumab

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced renal cell carcinoma (RCC). However, ICIs often induce immune-related adverse events (irAEs), which vary greatly among individuals and may influence treatment outcomes. This study aimed to identify genetic markers associated with the risk of severe treatment-related adverse events (trAEs) and assess their impact on patient prognosis. From August 19, 2019, to September 30, 2020, patient recruitment for nivolumab treatment in advanced clear cell RCC (ccRCC) was conducted across 23 institutions in Japan, with follow-up concluding on March 31, 2021 (protocol ID: UMIN000037739). A genome-wide association study (GWAS) was conducted in a development cohort to identify single nucleotide polymorphisms (SNPs) associated with severe trAEs following nivolumab. Sixteen SNPs were identified, and thirteen were genotyped in a validation cohort. Eight SNPs showed consistent trends with the development cohort, but they have not reached statistical significance in the validation cohort. Among them, rs2545737, corresponding to CHD1, was significantly linked to prolonged progression-free survival (PFS), highlighting its potential as a biomarker for both safety and efficacy. Further analysis indicated that high CHD1 expression in tumors correlated with improved overall survival in nivolumab-treated patients but not in those receiving everolimus. Given the failure to replicate the development set findings in our validation cohort, further re-validation within the RCC population is warranted. However, these results enhance our understanding of the genetic predisposition to trAEs and provide a significant step toward safer and more effective cancer treatment strategies. This study was registered on the University Hospital Medical Information Network (UMIN) in Japan on August 20, 2019 (protocol ID: UMIN000037739).

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Journal
Cancer Science
Published
2025-09-24
DOI
https://doi.org/10.1111/cas.70204
Primary Topic
Renal cell carcinoma treatment
Type
article
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article

GWAS Identifies SNPs Associated With Severe Adverse Events and Efficacy in Advanced Renal Cell Carcinoma Treated With Nivolumab

Masatoshi Eto, M Nozawa, Hideyasu Matsuyama, Yoshihiko Tomita et al.
Cancer Science
Renal cell carcinoma treatment
article

GWAS Identifies SNPs Associated With Severe Adverse Events and Efficacy in Advanced Renal Cell Carcinoma Treated With Nivolumab

Masatoshi Eto, M Nozawa, Hideyasu Matsuyama, Yoshihiko Tomita, Nobuo Shinohara, Masaki Shiota, Kiyohide Fujimoto, Norihiko Tsuchiya, Tokiyoshi Tanegashima, Shuichi Tatarano, Katsuyoshi Hashine, Wataru Obara, Momokazu Gotoh, Kojiro Ohba, Keiichi Ito, Masayuki Takahashi, Tomomi Kamba, Chikara Οhyama, Shusuke Akamatsu, Shoichiro Mukai, Naoya Masumori, Koji Mita, Mototsugu Oya, Hideaki Miyake, Shoji Tokunaga, Masato Fujisawa
article en

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced renal cell carcinoma (RCC). However, ICIs often induce immune-related adverse events (irAEs), which vary greatly among individuals and may influence treatment outcomes. This study aimed to identify genetic markers associated with the risk of severe treatment-related adverse events (trAEs) and assess their impact on patient prognosis. From August 19, 2019, to September 30, 2020, patient recruitment for nivolumab treatment in advanced clear cell RCC (ccRCC) was conducted across 23 institutions in Japan, with follow-up concluding on March 31, 2021 (protocol ID: UMIN000037739). A genome-wide association study (GWAS) was conducted in a development cohort to identify single nucleotide polymorphisms (SNPs) associated with severe trAEs following nivolumab. Sixteen SNPs were identified, and thirteen were genotyped in a validation cohort. Eight SNPs showed consistent trends with the development cohort, but they have not reached statistical significance in the validation cohort. Among them, rs2545737, corresponding to CHD1, was significantly linked to prolonged progression-free survival (PFS), highlighting its potential as a biomarker for both safety and efficacy. Further analysis indicated that high CHD1 expression in tumors correlated with improved overall survival in nivolumab-treated patients but not in those receiving everolimus. Given the failure to replicate the development set findings in our validation cohort, further re-validation within the RCC population is warranted. However, these results enhance our understanding of the genetic predisposition to trAEs and provide a significant step toward safer and more effective cancer treatment strategies. This study was registered on the University Hospital Medical Information Network (UMIN) in Japan on August 20, 2019 (protocol ID: UMIN000037739).

Cancer ScienceVol. 116(12)
Kagoshima University (JP), Yamagata University (JP), University of Miyazaki (JP), Kyushu University (JP), Sapporo Medical University (JP), Hirosaki University (JP), Yamaguchi University (JP), Iwate Medical University (JP), Keio University (JP), Hokkaido University (JP), Kyoto University (JP), Hamamatsu University School of Medicine (JP), Kindai University Hospital (JP), Kyushu University Hospital (JP), Hiroshima City Asa Citizens Hospital (JP), Shikoku Cancer Center (JP), Nagasaki University (JP), National Defense Medical College (JP), Nagoya University (JP), Nara Medical University (JP), Kobe University (JP), Niigata University (JP), Kindai University (JP), Tokushima University (JP), Kumamoto University (JP)
Bristol-Myers Squibb, Ono Pharmaceutical
Openalex Percentile: Top 63%
Renal cell carcinoma treatment
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