biostudies-literatureColli LMCancer Research UKU.S. Department of Health and Human ServicesNational Cancer InstituteNational Institute for Health Research (NIHR)National Institutes of HealthGovernment of South Australia1590-1610https://www.ebi.ac.uk/biostudies/studies/S-EPMC8456159biostudies-literatureUnknown108(9)Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complexAmerican journal of human geneticsAltered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus.PMC8456159RP-2015-06-00416016Cunha RChanock SJMachiela MJOnabajo OPurdue MPColli LMChoi JYu KBrown KMMyers TASchmid VBrodie SAMole DRJessop LCamp SYMills GCDelattre OfalseAltered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus.Our study investigated the underlying mechanism for the 14q24 renal cell carcinoma (RCC) susceptibility risk locus identified by a genome-wide association study (GWAS). The sentinel single-nucleotide polymorphism (SNP), rs4903064, at 14q24 confers an allele-specific effect on expression of the double PHD fingers 3 (DPF3) of the BAF SWI/SNF complex as assessed by massively parallel reporter assay, confirmatory luciferase assays, and eQTL analyses. Overexpression of DPF3 in renal cell lines increases growth rates and alters chromatin accessibility and gene expression, leading to inhibition of apoptosis and activation of oncogenic pathways. siRNA interference of multiple DPF3-deregulated genes reduces growth. Our results indicate that germline variation in DPF3, a component of the BAF complex2021-01-01T00:00:00Z2021 Sep2026-05-30T15:48:56.654Z2025-04-04T10:02:54.36ZS-EPMC84561593439065310.1016/j.ajhg.2021.07.009