Genome-wide association to identify SNPs associated with severe adverse events and clinical outcomes in advanced renal cell carcinoma treated with nivolumab.

520 Background: Immune checkpoint inhibitors (ICIs) have markedly changed the management of advanced renal cell carcinoma (RCC). However, ICIs frequently induce immune-related adverse events (irAEs), which vary widely among patients and may affect treatment outcomes. We conducted a genome-wide association study (GWAS) to explore genetic markers associated with severe treatment-related adverse events (trAEs) and to examine their potential impact on prognosis. Methods: Between August 2019 and September 2020, patients with advanced clear cell RCC (ccRCC) receiving nivolumab were enrolled at 23 institutions in Japan (protocol ID: UMIN000037739). Follow-up was completed in March 2021. A total of 223 patients were included: 113 in a development set and 110 in a validation set. GWAS was performed in the development cohort to identify single nucleotide polymorphisms (SNPs) associated with severe trAEs. Candidate SNPs were then assessed in the validation cohort, and their relationship with clinical outcomes was further explored. Results: Sixteen SNPs were associated with severe trAEs in the development set, of which thirteen were successfully genotyped in the validation set. Eight SNPs demonstrated consistent trends, although statistical significance was not reached. Notably, rs2545737 located in CHD1 was associated with prolonged progression-free survival (PFS). Additional analyses revealed that higher CHD1 expression correlated with improved overall survival in nivolumab-treated patients, but not in those receiving everolimus. Conclusions: Although findings from the development set were not fully replicated in the validation cohort, this study provides insights into the genetic predisposition to trAEs and highlights CHD1 as a potential biomarker linking treatment safety and efficacy. Further large-scale validation is warranted to confirm these observations.