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The Functionality of Prostate Cancer Predisposition Risk Regions Is Revealed by AR Enhancers

Abstract

Prostate Cancer (PCa) genetic risk has recently been defined in numerous genome-wide association studies (GWAS), which revealed more than 50 disease-associated single nucleotide polymorphisms (SNPs), known as tagSNPs, each at a different locus. More than 80% of these tagSNPs are located in noncoding regions of the genome for which functionality remains unknown. We and others hypothesize that at least some of these SNPs affect noncoding genomic regulatory signatures such as enhancers. Many research laboratories including ours have profiled the genomic distribution of androgen receptor (AR) and the dynamic state of the PCa genome for active chromatin regions (H3K9,14ac), open chromatin regions (DNaseI), enhancers (H3K4me1/2), and active/engaged enhancers (H3K27ac). In order to identify candidate functional SNPs, which may confer risk associated with PCa, we recently developed an open-source (R/Bioconductor) package, called FunciSNP (Functional Integration of SNPs), which systematically integrates SNPs from the 1000 genomes project with these biologically active chromatin features. Here we report several potential AR enhancers, defined by genome-wide data and from chromatin biofeatures, which may be functionally involved in PCa risk.

Keywords

  • Enhancer
  • Androgen Receptor Occupied Regions (ARORs)
  • Chromatin
  • Genome
  • Single Nucleotide Polymorphism
  • Post-GWAS function

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Abbreviations

AR:

Androgen receptor

DHT:

Dihydrotestosterone

ARE:

Anrogen responsive element

ARORs:

Androgen receptor occupied regions

GWAS:

Genome-wide association studies

1000gp:

1000 genomes project

SNP:

Single nucleotide polymorphisms

FunciSNP:

Functional Identification of SNPs

LD:

Linkage disequilibrium

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Acknowledgments

The authors thank Charles Nicolet at the USC Epigenome Center for library construction and high throughput sequencing.

Funding

Original work reported here was funded by the National Institutes of Health (NIH) [CA109147, U19CA148537 and U19CA148107 to G.A.C.; 5T32CA009320-27 to H.N.] and David Mazzone Awards Program (G.A.C). Additionally, some of the scientific development and funding of this project were supported by the Genetic Associations and Mechanisms in Oncology (GAME-ON): a NCI Cancer Post-GWAS Initiative.

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Correspondence to Gerhard A. Coetzee .

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Noushmehr, H., Coetzee, S.G., Rhie, S.K., Yan, C., Coetzee, G.A. (2013). The Functionality of Prostate Cancer Predisposition Risk Regions Is Revealed by AR Enhancers. In: Wang, Z. (eds) Androgen-Responsive Genes in Prostate Cancer. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-6182-1_5

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