Functional analysis of the chr13q22.1 pancreatic cancer risk locus suggests allele-specific effects on DIS3 expression. J. Hoskins1, A. Ibrahim1, H. Parikh1, J. Kim1, J. Jia1, I. Collins1, G. Petersen2, L. Amundadottir1 1) Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Gaithersburg, MD; 2) Mayo Clinic, Rochester, MN.

   Pancreatic cancer is the 10th most common cancer and 4th most common cause of cancer mortality in the United States. A genome wide association study revealed pancreatic cancer susceptibility loci on chromosomes 13q22.1, 1q32.1 and 5p15.33. The most significant single nucleotide polymorphism (SNP) identified in this GWAS, rs9543325, is located in chr13q22.1 within a gene desert. The nearest genes to rs9543325 are KLF5, KLF12, PIBF1, DIS3 and BORA, which range from 265kb to 586kb away, respectively. Given the high linkage disequilibrium across this risk locus, there are many candidate functional variants to consider. Imputations of these functional variants did not improve the signal, but produced a set of highly correlated SNPs. In an effort to identify the functional variant(s) we performed eQTL analyses to test the association between the genotypes of these candidate SNPs and expression of nearby genes. Among 100 normal pancreatic tissue samples, DIS3 showed the strongest association with a novel variant in the risk locus (P-value = 0.0004). Mutations in DIS3 have previously been identified in acute myeloid leukemia and multiple myeloma, and its expression has been correlated with metastatic potential in colorectal cancer, suggesting this gene could be important in pancreatic cancer biology. Chromosome conformation capture (3C) was performed to test for physical interactions between the risk locus and nearby genes. This assay confirmed the three dimensional proximity of the risk locus and a region near the DIS3 promoter. Finally, sub-regions of the risk locus were cloned upstream of a luciferase expression construct to assay for potential allele-specific enhancer/silencer activity. This assay revealed the sub-region containing the most significant DIS3 eQTL acts as an allele-specific silencer. Together, these results suggest that a sub-region of the chr13q22.1 pancreatic cancer risk locus has allele-specific effects on DIS3 expression, which may have implications in pancreatic cancer susceptibility.

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