Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression.
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 (β = 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.
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Jason W
JW
Hoskins
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Abdisamad
A
Ibrahim
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Mickey A
MA
Emmanuel
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Sarah M
SM
Manmiller
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Yinglun
Y
Wu
Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Maura
M
O'Neill
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Jinping
J
Jia
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Irene
I
Collins
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Mingfeng
M
Zhang
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Janelle V
JV
Thomas
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Lauren M
LM
Rost
Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Sudipto
S
Das
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Hemang
H
Parikh
Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
Jefferson M
JM
Haake
Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
Gail L
GL
Matters
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
Robert C
RC
Kurtz
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
William R
WR
Bamlet
Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA|Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland, USA
Alison
A
Klein
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Rachael
R
Stolzenberg-Solomon
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Brian M
BM
Wolpin
Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
Ronit
R
Yarden
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.|Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
Zhaoming
Z
Wang
Department of Medicine, Georgetown University Hospital, Washington, DC, and Department of Medicine, Penn State University College of Medicine, Hershey PA, USA.
Jill
J
Smith
Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
Sara H
SH
Olson
Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Thorkell
T
Andresson
Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
Gloria M
GM
Petersen
Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Laufey T
LT
Amundadottir
D000483:Alleles; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics / Q000378:metabolism; D002874:Chromosome Mapping / Q000379:methods; D002882:Chromosomes, Human, Pair 13; D063326:Exosome Multienzyme Ribonuclease Complex / Q000235:genetics* / Q000378:metabolism; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D054643:INDEL Mutation; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics
D002843:Chromatin; D014157:Transcription Factors; D063326:Exosome Multienzyme Ribonuclease Complex; C551543:DIS3 protein, human