Gene regulatory mechanisms underpinning prostate cancer susceptibility

Thomas Whitington, Ping Gao, Wei Song, Helen Ross-Adams, Alastair D Lamb, Yuehong Yang, Ilaria Svezia, Daniel Klevebring, Ian G Mills, Robert Karlsson, Silvia Halim, Mark J Dunning, Lars Egevad, Anne Y Warren, David E Neal, Henrik Grönberg, Johan Lindberg, Gong-Hong Wei, Fredrik Wiklund

Research output: Contribution to journalArticlepeer-review

59 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)387
Number of pages14
JournalNature Genetics
Volume48
Early online date07 Mar 2016
DOIs
Publication statusEarly online date - 07 Mar 2016

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