Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced renal cell carcinoma (RCC). However, ICI 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 irAEs 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 using a development cohort of 113 patients, followed by genotyping of individual single nucleotide polymorphism (SNP) in a validation cohort of 110 patients.

GWAS revealed that eight SNPs were associated with severe irAEs (Figure 1). Among them, rs2545737, corresponding to CHD1, was significantly linked to prolonged progression free survival (PFS) (Figure 2), 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. Conclusions This study identified eight SNPs associated with severe irAEs in patients with advanced ccRCC treated with nivolumab. Notably, rs2545737 was also found to be associated with prolonged PFS. Further validation in diverse populations and functional analyses of the identified SNPs are essential. These results enhance our understanding of the genetic predisposition to irAEs and provide a significant step toward safer and more effective cancer treatment strategies.

This study identified eight SNPs associated with severe irAEs in patients with advanced ccRCC treated with nivolumab. Notably, rs2545737 was also found to be associated with prolonged PFS. Further validation in diverse populations and functional analyses of the identified SNPs are essential. These results enhance our understanding of the genetic predisposition to irAEs and provide a significant step toward safer and more effective cancer treatment strategies.