Transcriptional regulation and prostate cancer risk loci

• Published in: Journal of clinical oncology Vol. 31; no. 15_suppl; p. 1554
• Main Authors: Klein, Robert J., Xu, Xing, Hussain, Wasay, Farber, James, Vaananen, Riina-Minna, Taimen, Pekka, Vijai, Joseph, Hayes, James E., Lilja, Hans, Pettersson, Kim, Rubin, Mark A., Demichelis, Francesca, Offit, Kenneth
• Format: Journal Article
• Language: English
• Published: 20.05.2013
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/jco.2013.31.15_suppl.1554

Abstract only 1554 Background: While genome-wide association studies (GWAS) have identified numerous loci at which common single nucleotide polymorphisms (SNPs) are clearly associated with the risk of developing prostate cancer, the mechanism by which these variants influence disease is not clear. Based on the observation that regions of the genome with marks of transcriptional regulatory elements harbor SNPs that are more likely to be under negative selective pressure, we hypothesized that many prostate cancer associated SNPs, or their correlated proxies in linkage disequilibrium, function by altering regulation of nearby genes through alteration of transcription factor binding sites. Two predictions of this hypothesis are that there will be an enrichment of prostate cancer risk SNPs or their proxies in regulatory elements in prostate tissue and that some of these SNPs will correlate with the expression levels of nearby genes. Methods: To test the first prediction, we compared the number of prostate cancer risk SNPs (or their proxies) that overlap with DNase hypersensitive sites in the LNCaP prostate cancer cell line with randomly selected SNPs matched for allele frequency, distance from nearby genes, and local gene density. To test the second prediction, we asked if any of the known prostate cancer risk SNPs are associated with mRNA expression levels of nearby genes. Results: We found a four-fold enrichment of real prostate cancer risk SNPs overlapping with DNase hypersensitive sites versus the random set (p=0.03) at an r 2 threshold of 0.95. In both tumor and benign prostate tissue, we found that a recently identified prostate cancer risk SNP is associated with expression levels of IRX4, a transcription factor previously implicated only in cardiac development. Conclusions: These data support the hypothesis that many GWAS-identified risk SNPs alter transcriptional regulation of nearby genes.