Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression Journal Article
| Authors: | Hoskins, J. W.; Ibrahim, A.; Emmanuel, M. A.; Manmiller, S. M.; Wu, Y.; O'Neill, M.; Jia, J.; Collins, I.; Zhang, M.; Thomas, J. V.; Rost, L. M.; Das, S.; Parikh, H.; Haake, J. M.; Matters, G. L.; Kurtz, R. C.; Bamlet, W. R.; Klein, A.; Stolzenberg-Solomon, R.; Wolpin, B. M.; Yarden, R.; Wang, Z.; Smith, J.; Olson, S. H.; Andresson, T.; Petersen, G. M.; Amundadottir, L. T. |
| Article Title: | Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression |
| Abstract: | Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P=2.30×10-11, OR=1.22, 95% CI 1.15-1.28) and highly correlated to rs9543325 (r2=0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (b=0.26, P=0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region ~6 kb upstream of DIS3. Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay. © The Author 2016. Published by Oxford University Press. |
| Journal Title: | Human Molecular Genetics |
| Volume: | 25 |
| Issue: | 21 |
| ISSN: | 0964-6906 |
| Publisher: | Oxford University Press |
| Date Published: | 2016-11-01 |
| Start Page: | 4726 |
| End Page: | 4738 |
| Language: | English |
| DOI: | 10.1093/hmg/ddw300 |
| PROVIDER: | scopus |
| PUBMED: | 28172817 |
| PMCID: | PMC5815622 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 April 2017 -- Source: Scopus |
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