Abstract
Abstract We have previously reported an association between prostate cancer (PrCa) risk and rs2242652 on 5p15. rs2242652 lies in intron 4 of TERT, which encodes telomerase reverse transcriptase, the catalytic subunit of the telomerase ribonucleoprotein complex. Telomerase catalyzes the de novo addition of telomere repeat sequences on to chromosome ends and thereby counterbalances telomere-dependent replicative senescence. Associations between SNPs in the TERT region and multiple cancer types have been reported; however no correlation has been observed thus far between the cancer-associated SNPs in TERT and gene expression or telomere length. To comprehensively evaluate the association between genetic variation across this region and PrCa we performed a fine-mapping analysis by direct genotyping using either a custom Illumina iSelect array (114 SNPs on iCOGS) or Sequenom MassArray iPlex (25 SNPs) followed by imputation of 1,094 SNPs in 22,301 PrCa cases and 22,320 controls in the PRACTICAL consortium. To determine independently associated variants in this region, we performed multiple stepwise logistic regression analysis; SNPs were included in the model if they were significant at P<10−4 after adjustment for other SNPs. Regression models identified multiple independent associations, reflecting the complexity of this region. These SNPs fall into four regions consisting of clusters of highly or moderately correlated variants, and there is only weak LD between SNPs in different regions. To investigate whether SNPs in any of these regions were associated with TERT gene expression, we performed qPCR assays on RNA from benign prostate tissue samples using the Fluidigm Biomark™ HD system. We found evidence that the risk reducing alleles of several variants in region one associated with elevated TERT expression, providing a plausible mechanism for the differential effect of SNPs on PrCa risk. Deep re-sequencing of these loci may help to further refine this region and facilitate selection of prospective causal variants for functional validation studies. Citation Format: Zsofia Kote-Jarai, Edward Saunders, Daniel Leongamornlert, Malgorzata Tymrakiewicz, Tokhir Dadaev, Sarah Jugurnauth, Sara Benlloch, Ali Amin Al Olama, Helen Ross-Adams, David Neal, The UKGPCS Collaborators and The PRACTICAL Consortium, Douglas Easton, Rosalind Eeles. Fine-mapping identifies multiple prostate cancer risk loci at 5p15, one of which associates with TERT expression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2546. doi:10.1158/1538-7445.AM2013-2546
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