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

Tokiyoshi Tanegashima1, Masaki Shiota1, Shusuke Akamatsu2

  • 1Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Cancer Science
|September 24, 2025
PubMed

Insights

Genetic markers like CHD1 may predict severe side effects and improve outcomes for advanced renal cell carcinoma (RCC) patients treated with immune checkpoint inhibitors (ICIs). Further validation is needed for these safety and efficacy biomarkers.

Area of Science:

  • Oncology
  • Immunotherapy
  • Genetics

Background:

  • Immune checkpoint inhibitors (ICIs) have transformed advanced renal cell carcinoma (RCC) treatment.
  • Immune-related adverse events (irAEs) from ICIs vary individually and can impact outcomes.
  • Identifying genetic markers for severe treatment-related adverse events (trAEs) is crucial for personalized medicine.

Purpose of the Study:

  • To identify genetic markers associated with severe trAEs in advanced clear cell RCC (ccRCC) patients receiving nivolumab.
  • To evaluate the impact of identified genetic markers on patient prognosis, including progression-free survival (PFS) and overall survival (OS).
  • To explore the potential of genetic variations as biomarkers for both safety and efficacy of ICI treatment.

Main Methods:

  • A genome-wide association study (GWAS) was performed on a development cohort of advanced ccRCC patients treated with nivolumab.
  • Sixteen single nucleotide polymorphisms (SNPs) associated with severe trAEs were identified in the development cohort.
  • Thirteen SNPs were genotyped in a validation cohort; eight showed consistent trends, with rs2545737 (CHD1) showing a significant link to prolonged PFS.

Main Results:

  • While most identified SNPs did not reach statistical significance in the validation cohort, rs2545737 (CHD1) was significantly associated with prolonged PFS.
  • High CHD1 expression in tumors correlated with improved overall survival in nivolumab-treated patients, but not in those receiving everolimus.
  • The study identified a potential genetic predisposition to trAEs, though replication in the validation cohort was limited, necessitating further re-validation.

Conclusions:

  • The rs2545737 SNP, corresponding to CHD1, shows potential as a biomarker for predicting both safety and efficacy in advanced ccRCC patients treated with nivolumab.
  • These findings contribute to understanding the genetic basis of trAEs and offer a step towards safer, more effective cancer immunotherapy.
  • Further re-validation studies within the RCC population are warranted to confirm these promising biomarker candidates.
Keywords:
anti‐PD‐1 antibodygenome‐wide association studynivolumabrenal cell carcinomasingle nucleotide polymorphismtreatment‐related adverse event

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