Genomic Enhancers at 8q24 and Prostate Cancer The understanding of genetic predisposition to prostate cancer (PCa) and the identification of at-risk alleles have undergone a revolution during the past three years, mainly due to the utilization of high-throughput genomic technologies. For example, in a comprehensive multi-ethnic study of germline variation and PCa risk, we established multiple independent risk alleles in 3 regions that span ~500-kb on chromosome 8q24. The alleles were verified in many other subsequent studies. All the variants are located in non-protein coding sequences and are >200-kb from any known gene. A 5-Mb chromatin segment encompassing all the risk regions was profiled for RNA expression, histone modifications and locations occupied by RNA polymerase II and the androgen receptor. This led to the identification of transcriptional enhancers, which were verified using reporter assays. In two of them single nucleotide polymorphisms (SNPs) affected TCF7L2 and FoxA1 binding, respectively and in the latter androgen-dependent enhancer activity. Our overall hypothesis is: PCa predisposition at 8q24 is governed by SNPs in enhancers, which affect transcription factor binding and distant gene expression.
In specific aim #1, the enhancers containing risk SNPs will be characterized in vitro with emphasis on how genetic variations affect the combinatorial regulation of enhancer activities (subaim 1.1). Special attention will be directed towards already-identified, TCF7L2-, FoxA1- and androgen receptor-mediated risk mechanisms. Additionally, in vivo enhancer activities will be investigated in mice carrying reporter genes controlled by candidate enhancer elements (subaim 1.2). The spatial and temporal pattern of reporter activity will disclose the cell types and developmental stages at which the risk SNP-containing enhancers are maximally operative and how these patterns are modified by the risk SNPs.
In specific aim #2, we will identify the target genes of the enhancers. We intend to employ three approaches: (i) large bacterial artificial chromosomes to test alleles under different physiologic conditions in cell culture and in mice (subaim 2.1), (ii) chromatin looping assays to test candidate target genes (such as Myc) (submain 2.2) and (iii) an unbiased looping screen to identify novel target genes genome-wide (subaim 2.3). Successful completion of the aims will lead to a more complete understanding of the biological mechanisms underlying genetic associations with PCa risk, as observed with variants located in non-protein coding sequences at 8q24. Additionally, our approach may provide a novel paradigm to study many other genetic loci found in non-protein coding areas associated with other disease states.

Public Health Relevance

Genomic Enhancers at 8q24 and Prostate Cancer This project seeks to unravel fundamental mechanisms of prostate cancer risk, one of the most wide spread cancers in the U.S and the world;it is estimated that in the U.S. alone ~200,000 men are diagnosed annually with prostate cancer and ~27,000 die each year from the disease. Men from African ancestry have nearly twice the risk for prostate cancer development than men from other racial-ethnic groups and genetic factors probably significantly contribute to this increase. We have previously shown that an area of 500,000 base pairs (consecutive DNA 'letters') on human chromosome 8 is robustly involved in prostate cancer predisposition/risk and in this application will expose exactly how (mechanism) this is brought about.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Cancer Genetics Study Section (CG)
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Sathyamoorthy, Neeraja
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University of Southern California
Schools of Medicine
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(2016) Functional mechanisms underlying pleiotropic risk alleles at the 19p13.1 breast-ovarian cancer susceptibility locus. Nat Commun 7:12675
Amos, Christopher I; Dennis, Joe; Wang, Zhaoming et al. (2016) The OncoArray Consortium: A Network for Understanding the Genetic Architecture of Common Cancers. Cancer Epidemiol Biomarkers Prev :
Cai, Mingyang; Kim, Sewoon; Wang, Kai et al. (2016) 4C-seq revealed long-range interactions of a functional enhancer at the 8q24 prostate cancer risk locus. Sci Rep 6:22462
Song, Xiaofeng; Zhang, Naibo; Han, Ping et al. (2016) Circular RNA profile in gliomas revealed by identification tool UROBORUS. Nucleic Acids Res 44:e87
Rhie, Suhn Kyong; Guo, Yu; Tak, Yu Gyoung et al. (2016) Identification of activated enhancers and linked transcription factors in breast, prostate, and kidney tumors by tracing enhancer networks using epigenetic traits. Epigenetics Chromatin 9:50
Cuellar-Partida, Gabriel; Lu, Yi; Dixon, Suzanne C et al. (2016) Assessing the genetic architecture of epithelial ovarian cancer histological subtypes. Hum Genet 135:741-56
Hazelett, Dennis J; Conti, David V; Han, Ying et al. (2016) Reducing GWAS Complexity. Cell Cycle 15:22-4
Cai, Mingyang; Gao, Fan; Lu, Wange et al. (2016) w4CSeq: software and web application to analyze 4C-seq data. Bioinformatics 32:3333-3335
Lee, Alice W; Templeman, Claire; Stram, Douglas A et al. (2016) Evidence of a genetic link between endometriosis and ovarian cancer. Fertil Steril 105:35-43.e1-10
Tak, Yu Gyoung; Hung, Yuli; Yao, Lijing et al. (2016) Effects on the transcriptome upon deletion of a distal element cannot be predicted by the size of the H3K27Ac peak in human cells. Nucleic Acids Res 44:4123-33

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