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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA136924-05
Application #
8606425
Study Section
Cancer Genetics Study Section (CG)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2010-02-23
Project End
2015-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
5
Fiscal Year
2014
Total Cost
$370,857
Indirect Cost
$107,249
Name
University of Southern California
Department
Urology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Kelemen, Linda E; Terry, Kathryn L; Goodman, Marc T et al. (2014) Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk. Mol Nutr Food Res 58:2023-35
Block, Matthew S; Charbonneau, Bridget; Vierkant, Robert A et al. (2014) Variation in NF-?B signaling pathways and survival in invasive epithelial ovarian cancer. Cancer Epidemiol Biomarkers Prev 23:1421-7
Cozen, W; Timofeeva, M N; Li, D et al. (2014) A meta-analysis of Hodgkin lymphoma reveals 19p13.3 TCF3 as a novel susceptibility locus. Nat Commun 5:3856
Rhie, Suhn Kyong; Hazelett, Dennis J; Coetzee, Simon G et al. (2014) Nucleosome positioning and histone modifications define relationships between regulatory elements and nearby gene expression in breast epithelial cells. BMC Genomics 15:331
Al Olama, Ali Amin; Kote-Jarai, Zsofia; Berndt, Sonja I et al. (2014) A meta-analysis of 87,040 individuals identifies 23 new susceptibility loci for prostate cancer. Nat Genet 46:1103-9
Earp, Madalene A; Kelemen, Linda E; Magliocco, Anthony M et al. (2014) Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA. Hum Genet 133:481-97
Charbonneau, Bridget; Moysich, Kirsten B; Kalli, Kimberly R et al. (2014) Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome. Cancer Immunol Res 2:332-40
Hazelett, Dennis J; Coetzee, Simon G; Coetzee, Gerhard A (2013) A rare variant, which destroys a FoxA1 site at 8q24, is associated with prostate cancer risk. Cell Cycle 12:379-80
Rhie, Suhn Kyong; Coetzee, Simon G; Noushmehr, Houtan et al. (2013) Comprehensive functional annotation of seventy-one breast cancer risk Loci. PLoS One 8:e63925
Trotta, Andrew P; Need, Eleanor F; Selth, Luke A et al. (2013) Knockdown of the cochaperone SGTA results in the suppression of androgen and PI3K/Akt signaling and inhibition of prostate cancer cell proliferation. Int J Cancer 133:2812-23

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