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
This is a preview of subscription content, log in via an institution.
Buying options
Tax calculation will be finalised at checkout
Purchases are for personal use only
Learn about institutional subscriptionsAbbreviations
- 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
References
Visscher PM et al (2012) Five years of GWAS discovery. Am J Hum Genet 90(1):7–24
Hindorff LA et al (2009) Potential etiologic and functional implications of genome-wide association loci for human diseases and traits. Proc Natl Acad Sci USA 106(23):9362–9367
Coetzee SG et al (2012) FunciSNP: an R/bioconductor tool integrating functional non-coding data sets with genetic association studies to identify candidate regulatory SNPs. Nucl Acids Res 40:e139
Coetzee GA (2012) The usefulness of prostate cancer genome-wide association studies. J Urol 187(1):9–10
Coetzee GA et al (2010) A systematic approach to understand the functional consequences of non-protein coding risk regions. Cell Cycle 9(2):47–51
Heinlein CA, Chang C (2004) Androgen receptor in prostate cancer. Endocr Rev 25(2):276–308
Bluemn EG, Nelson PS (2012) The androgen/androgen receptor axis in prostate cancer. Curr Opin Oncol 24(3):251–257
Denmeade SR, Isaacs JT (2002) A history of prostate cancer treatment. Nat Rev Cancer 2(5):389–396
Cai C, Balk SP (2011) Intratumoral androgen biosynthesis in prostate cancer pathogenesis and response to therapy. Endocr Relat Cancer 18(5):R175–R182
Lonergan PE, Tindall DJ (2011) Androgen receptor signaling in prostate cancer development and progression. J Carcinog 10:20
Montgomery RB et al (2008) Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res 68(11):4447–4454
Mostaghel EA et al (2010) Variability in the androgen response of prostate epithelium to 5alpha-reductase inhibition: implications for prostate cancer chemoprevention. Cancer Res 70(4):1286–1295
(2011) Triple-acting drug boosts prostate cancer survival. Cancer Discov 1(7): OF1
Tran C et al (2009) Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 324(5928):787–790
Mukherji D, Pezaro CJ, De-Bono JS (2012) MDV3100 for the treatment of prostate cancer. Expert Opin Investig Drugs 21(2):227–233
Grasso CS et al (2012) The mutational landscape of lethal castration-resistant prostate cancer. Nature 487:239–243
Chen Y et al (2012) Systematic evaluation of factors influencing ChIP-seq fidelity. Nat Methods 9:609–614
Qin B et al (2012) CistromeMap: a knowledgebase and web server for ChIP-Seq and DNase-Seq studies in mouse and human. Bioinformatics 28(10):1411–1412
Lupien M et al (2008) FoxA1 translates epigenetic signatures into enhancer-driven lineage-specific transcription. Cell 132(6):958–970
Andreu-Vieyra C et al (2011) Dynamic nucleosome-depleted regions at androgen receptor enhancers in the absence of ligand in prostate cancer cells. Mol Cell Biol 31(23):4648–4662
Wang Q et al (2009) Androgen receptor regulates a distinct transcription program in androgen-independent prostate cancer. Cell 138(2):245–256
Wang D et al (2011) Reprogramming transcription by distinct classes of enhancers functionally defined by eRNA. Nature 474(7351):390–394
Zhang C et al (2011) Definition of a FoxA1 Cistrome that is crucial for G1 to S-phase cell-cycle transit in castration-resistant prostate cancer. Cancer Res 71(21):6738–6748
Dryhurst D et al (2012) Histone H2A.Z prepares the prostate specific antigen (PSA) gene for androgen receptor-mediated transcription and is upregulated in a model of prostate cancer progression. Cancer Lett 315(1):38–47
Cai C et al (2011) Androgen receptor gene expression in prostate cancer is directly suppressed by the androgen receptor through recruitment of lysine-specific demethylase 1. Cancer Cell 20(4):457–471
Sahu B et al (2011) Dual role of FoxA1 in androgen receptor binding to chromatin, androgen signalling and prostate cancer. EMBO J 30(19):3962–3976
Taslim C et al (2012) Integrated analysis identifies a class of androgen-responsive genes regulated by short combinatorial long-range mechanism facilitated by CTCF. Nucleic Acids Res 40(11):4754–4764
Song L et al (2011) Open chromatin defined by DNaseI and FAIRE identifies regulatory elements that shape cell-type identity. Genome Res 21(10):1757–1767
He HH et al (2012) Differential DNase I hypersensitivity reveals factor-dependent chromatin dynamics. Genome Res 22(6):1015–1025
Myers RM et al (2011) A user’s guide to the encyclopedia of DNA elements (ENCODE). PLoS Biol 9(4):e1001046
Rivera A et al (2005) Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk. Hum Mol Genet 14(21):3227–3236
Hosking FJ, Dobbins SE, Houlston RS (2011) Genome-wide association studies for detecting cancer susceptibility. Br Med Bull 97:27–46
Park JH et al (2010) Estimation of effect size distribution from genome-wide association studies and implications for future discoveries. Nat Genet 42(7):570–575
Kruglyak L (2008) The road to genome-wide association studies. Nat Rev Genet 9(4):314–318
Hirschhorn JN, Daly MJ (2005) Genome-wide association studies for common diseases and complex traits. Nat Rev Genet 6(2):95–108
Hardy J, Singleton A (2009) Genomewide association studies and human disease. N Engl J Med 360(17):1759–1768
International HapMap Consortium (2003) The International HapMap Project. Nature 426(6968):789–796
Pennisi E (2010) Genomics. 1000 Genomes Project gives new map of genetic diversity. Science 330(6004):574–575
Consortium TGP (2010) A map of human genome variation from population-scale sequencing. Nature 467(7319):1061–1073
Freedman ML et al (2011) Principles for the post-GWAS functional characterization of cancer risk loci. Nat Genet 43(6):513–518
Rosenbloom KR et al (2011) ENCODE whole-genome data in the UCSC Genome Browser: update 2012. Nucl Acids Res 40:D912–D917
Jia L et al (2009) Functional enhancers at the gene-poor 8q24 cancer-linked locus. PLoS Genet 5(8):e1000597
Heinz S et al (2010) Simple combinations of lineage-determining transcription factors prime cis-regulatory elements required for macrophage and B cell identities. Mol Cell 38(4):576–589
Takata R et al (2010) Genome-wide association study identifies five new susceptibility loci for prostate cancer in the Japanese population. Nat Genet 42(9):751–754
Eeles RA et al (2009) Identification of seven new prostate cancer susceptibility loci through a genome-wide association study. Nat Genet 41(10):1116–1121
Kote-Jarai Z et al (2011) Seven prostate cancer susceptibility loci identified by a multi-stage genome-wide association study. Nat Genet 43(8):785–791
Schumacher FR et al (2011) Genome-wide association study identifies new prostate cancer susceptibility loci. Hum Mol Genet 20(19):3867–3875
Murabito JM et al (2007) A genome-wide association study of breast and prostate cancer in the NHLBI’s Framingham Heart Study. BMC Med Genet 8(Suppl 1):S6
Gudmundsson J et al (2009) Genome-wide association and replication studies identify four variants associated with prostate cancer susceptibility. Nat Genet 41(10):1122–1126
Eeles RA et al (2008) Multiple newly identified loci associated with prostate cancer susceptibility. Nat Genet 40(3):316–321
Thomas G et al (2008) Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet 40(3):310–315
Zheng SL et al (2007) Association between two unlinked loci at 8q24 and prostate cancer risk among European Americans. J Natl Cancer Inst 99(20):1525–1533
Yeager M et al (2007) Genome-wide association study of prostate cancer identifies a second risk locus at 8q24. Nat Genet 39(5):645–649
Gudmundsson J et al (2007) Genome-wide association study identifies a second prostate cancer susceptibility variant at 8q24. Nat Genet 39(5):631–637
Duggan D et al (2007) Two genome-wide association studies of aggressive prostate cancer implicate putative prostate tumor suppressor gene DAB2IP. J Natl Cancer Inst 99(24):1836–1844
Liu H, Wang B, Han C (2011) Meta-analysis of genome-wide and replication association studies on prostate cancer. Prostate 71(2):209–224
Chung CC et al (2011) Fine mapping of a region of chromosome 11q13 reveals multiple independent loci associated with risk of prostate cancer. Hum Mol Genet 20(14):2869–2878
Zheng SL et al (2009) Two independent prostate cancer risk-associated Loci at 11q13. Cancer Epidemiol Biomarkers Prev 18(6):1815–1820
Bonilla C et al (2011) Prostate cancer susceptibility Loci identified on chromosome 12 in African Americans. PLoS One 6(2):e16044
Sun J et al (2008) Evidence for two independent prostate cancer risk-associated loci in the HNF1B gene at 17q12. Nat Genet 40(10):1153–1155
Haiman CA et al (2011) Genome-wide association study of prostate cancer in men of African ancestry identifies a susceptibility locus at 17q21. Nat Genet 43(6):570–573
Hsu FC et al (2009) A novel prostate cancer susceptibility locus at 19q13. Cancer Res 69(7):2720–2723
Sun J et al (2009) Sequence variants at 22q13 are associated with prostate cancer risk. Cancer Res 69(1):10–15
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.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media, LLC
About this chapter
Cite this chapter
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
Download citation
DOI: https://doi.org/10.1007/978-1-4614-6182-1_5
Published:
Publisher Name: Springer, New York, NY
Print ISBN: 978-1-4614-6181-4
Online ISBN: 978-1-4614-6182-1
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)