Functional enhancers at the gene-poor 8q24 cancer-linked locus

Li Jia*, Gilad Landan, Mark Pomerantz, Rami Jaschek, Paula Herman, David Reich, Chunli Yan, Omar Khalid, Phil Kantoff, William Oh, J. Robert Manak, Benjamin P. Berman, Brian E. Henderson, Baruch Frenkel, Christopher A. Haiman, Matthew Freedman, Amos Tanay, Gerhard A. Coetzee

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

203 Scopus citations

Abstract

Multiple discrete regions at 8q24 were recently shown to contain alleles that predispose to many cancers including prostate, breast, and colon. These regions are far from any annotated gene and their biological activities have been unknown. Here we profiled a 5-megabase chromatin segment encompassing all the risk regions for RNA expression, histone modifications, and locations occupied by RNA polymerase II and androgen receptor (AR). This led to the identification of several transcriptional enhancers, which were verified using reporter assays. Two enhancers in one risk region were occupied by AR and responded to androgen treatment; one contained a single nucleotide polymorphism (rs11986220) that resides within a FoxA1 binding site, with the prostate cancer risk allele facilitating both stronger FoxA1 binding and stronger androgen responsiveness. The study reported here exemplifies an approach that may be applied to any risk-associated allele in nonprotein coding regions as it emerges from genome-wide association studies to better understand the genetic predisposition of complex diseases.

Original languageAmerican English
Article numbere1000597
JournalPLoS Genetics
Volume5
Issue number8
DOIs
StatePublished - Aug 2009
Externally publishedYes

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