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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 complex, part of the SWI/SNF complexes, can lead to reduced apoptosis and activation of the STAT3 pathway, both critical in RCC carcinogenesis. In addition, we show that altered DPF3 expression in the 14q24 RCC locus could influence the effectiveness of immunotherapy treatment for RCC by regulating tumor cytokine secretion and immune cell activation.

Original publication




Journal article


American journal of human genetics

Publication Date





1590 - 1610


Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD 20850, USA; Department of Medical Imaging, Hematology, and Oncology, Ribeirao Preto Medical School, University of Sao Paulo, Ribeirao Preto, SP 14040-900, Brazil.


T-Lymphocytes, Cytotoxic, Cell Line, Tumor, Chromosomes, Human, Pair 14, Chromatin, Humans, Carcinoma, Renal Cell, Kidney Neoplasms, Genetic Predisposition to Disease, DNA-Binding Proteins, Transcription Factors, Cytokines, Immunotherapy, Chromatin Assembly and Disassembly, Gene Expression Regulation, Polymorphism, Single Nucleotide, Genome, Human, STAT3 Transcription Factor, Genome-Wide Association Study, Genetic Loci, High-Throughput Nucleotide Sequencing, Carcinogenesis