Integrated analysis uncovers KCMF1 genetic susceptibility and the SNRPD2 axis in renal cell carcinoma

The ZZ-type zinc-finger family has emerged as an important regulator of tumorigenesis; however, its roles in renal cell carcinoma (RCC) susceptibility and prognosis are largely unexplored. This study aimed to systematically evaluate the genetic variants within this gene family to identify novel risk drivers and elucidate their downstream pathogenic networks. A total of 148 single-nucleotide polymorphisms (SNPs) were genotyped across 17 ZZ-type zinc finger genes in a cohort of 630 Taiwanese participants (312 patients with RCC and 318 healthy controls). The results were validated using pooled transcriptomic analysis of 18 independent datasets. Weighted gene co-expression network analysis (WGCNA) was used to construct tumor-specific networks and identify key driver genes. The Asian-specific variant of KCMF1 rs146409312 emerged as a significant susceptibility locus. The minor A allele conferred a 3.38-fold increased risk of RCC (adjusted odds ratio = 3.22, 95% confidence interval = 1.57-6.58, p = 0.001). KCMF1 was consistently upregulated in tumor tissues and was associated with poor patient survival. WGCNA identified a clinically relevant KCMF1-associated gene module enriched in ribosomal biogenesis and MYC target signaling. Within this network, SNRPD2 was identified as a critical hub gene, and its overexpression was strongly correlated with advanced tumor grade, stage, and reduced overall survival (p < 0.001). In conclusion, KCMF1 rs146409312 was identified as a potent, population-specific risk factor for RCC. A pathogenic KCMF1-driven network converging on SNRPD2 was delineated, offering novel insights into RCC etiology and highlighting potential biomarkers for prognostic stratification.