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Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression.
Pubmed ID
28172817 (View this publication on the PubMed website)
Digital Object Identifier
Hum. Mol. Genet. 2016 Nov 1; Volume 25 (Issue 21): Pages 4726-4738
Hoskins JW, Ibrahim A, Emmanuel MA, Manmiller SM, Wu Y, O'Neill M, Jia J, Collins I, Zhang M, Thomas JV, Rost LM, Das S, Parikh H, Haake JM, Matters GL, Kurtz RC, Bamlet WR, Klein A, Stolzenberg-Solomon R, Wolpin BM, more Yarden R, Wang Z, Smith J, Olson SH, Andresson T, Petersen GM, Amundadottir LT
  • Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
  • Department of Human Science, NHS, Georgetown University Medical Center, NW, Washington DC, USA.
  • Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
  • Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA.
  • Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
  • Department of Medicine, Georgetown University Hospital, Washington, DC, and Department of Medicine, Penn State University College of Medicine, Hershey PA, USA. more
  • Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

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.

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