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Gene regulatory mechanisms underpinning prostate cancer susceptibility
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Journal Article
Gene regulatory mechanisms underpinning prostate cancer susceptibility
2016
Overview
Thomas Whitington and colleagues present a detailed characterization of gene regulatory mechanisms underlying prostate cancer susceptibility. Their analysis highlights key mechanisms altered by disease-associated SNPs, including widespread disruption of ternary complexes involving AR, FOXA1 and HOXB13.
Molecular characterization of genome-wide association study (GWAS) loci can uncover key genes and biological mechanisms underpinning complex traits and diseases. Here we present deep, high-throughput characterization of gene regulatory mechanisms underlying prostate cancer risk loci. Our methodology integrates data from 295 prostate cancer chromatin immunoprecipitation and sequencing experiments with genotype and gene expression data from 602 prostate tumor samples. The analysis identifies new gene regulatory mechanisms affected by risk locus SNPs, including widespread disruption of ternary androgen receptor (AR)-FOXA1 and AR-HOXB13 complexes and competitive binding mechanisms. We identify 57 expression quantitative trait loci at 35 risk loci, which we validate through analysis of allele-specific expression. We further validate predicted regulatory SNPs and target genes in prostate cancer cell line models. Finally, our integrated analysis can be accessed through an interactive visualization tool. This analysis elucidates how genome sequence variation affects disease predisposition via gene regulatory mechanisms and identifies relevant genes for downstream biomarker and drug development.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ 45/43
/ Animal Genetics and Genomics
/ DNA
/ Gene Expression Regulation, Neoplastic
/ Genetic Predisposition to Disease
/ Genome-wide association studies
/ Genome-Wide Association Study
/ Genomes
/ Genomics
/ Grants
/ Humans
/ Identification and classification
/ Male
/ Methods
/ Polymorphism, Single Nucleotide
/ Prostatic Neoplasms - genetics
/ Prostatic Neoplasms - metabolism
/ Repressor Proteins - metabolism
/ Studies
