TY - JOUR
T1 - Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression
AU - Hoskins, Jason W.
AU - Ibrahim, Abdisamad
AU - Emmanuel, Mickey A.
AU - Manmiller, Sarah M.
AU - Wu, Yinglun
AU - O'Neill, Maura
AU - Jia, Jinping
AU - Collins, Irene
AU - Zhang, Mingfeng
AU - Thomas, Janelle V.
AU - Rost, Lauren M.
AU - Das, Sudipto
AU - Parikh, Hemang
AU - Haake, Jefferson M.
AU - Matters, Gail L.
AU - Kurtz, Robert C.
AU - Bamlet, William R.
AU - Klein, Alison
AU - Stolzenberg-Solomon, Rachael
AU - Wolpin, Brian M.
AU - Yarden, Ronit
AU - Wang, Zhaoming
AU - Smith, Jill
AU - Olson, Sara H.
AU - Andresson, Thorkell
AU - Petersen, Gloria M.
AU - Amundadottir, Laufey T.
N1 - Funding Information:
We thank the patients and donors of tissue and DNA samples that made this study possible. We are grateful to staff at Mayo Clinic (Rochester, MN), Memorial Sloan Kettering Cancer Center (New York City, NY) and Penn State College of Medicine (Hershey, PA) for help with tissue collection and processing. We are also grateful to staff at the Cancer Genomics Research Laboratory (CGR) at the National Cancer Institute, NIH, for their help with array genotyping. This work was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government.
Publisher Copyright:
© The Author 2016. Published by Oxford University Press.
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/ddw300
DO - 10.1093/hmg/ddw300
M3 - Article
C2 - 28172817
AN - SCOPUS:85014843250
VL - 25
SP - 4726
EP - 4738
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 21
ER -