Leandro M. Colli, Lea Jessop, Timothy A. Myers, Sabrina Y. Camp, Mitchell J. Machiela et al.
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.
Leandro M. Colli, Lea Jessop, Timothy A. Myers, Sabrina Y. Camp, Mitchell J. Machiela, Jiyeon Choi, Renato Cunha, Olusegun Onabajo, Grace C. Mills, Virginia Schmid, Seth A. Brodie, Olivier Delattre, David R. Mole, Mark P. Purdue, Kai Yu, Kevin M. Brown, Stephen J. Chanock. Altered regulation of DPF3, a member of the SWI/SNF complexes, underlies the 14q24 renal cancer susceptibility locus. 2021-08-13. https://doi.org/10.1016/j.ajhg.2021.07.009
A plasmid-based MPRA tested 39 linkage-disequilibrium-linked candidate SNPs in the 14q24 renal cell carcinoma susceptibility locus, with alternative alleles represented by barcoded forward and reverse constructs. Reporter RNA/DNA signals were modeled jointly across ACHN and HEK293T cells under normoxia and 1% oxygen hypoxia.
Original supplemental and deposited inputs retained for this study. Download files individually or together as a ZIP; nested folders are preserved. Source reuse terms apply, and sequencing reads may be omitted.
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