Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression

Hum Mol Genet. 2016 Nov 1;25(21):4726-4738. doi: 10.1093/hmg/ddw300.

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 (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.

MeSH terms

  • Alleles
  • Cell Line, Tumor
  • Chromatin / genetics
  • Chromatin / metabolism
  • Chromosome Mapping / methods
  • Chromosomes, Human, Pair 13*
  • Exosome Multienzyme Ribonuclease Complex / genetics*
  • Exosome Multienzyme Ribonuclease Complex / metabolism
  • Genetic Loci
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • INDEL Mutation
  • Pancreatic Neoplasms / enzymology
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Sequence Analysis, DNA
  • Transcription Factors / genetics

Substances

  • Chromatin
  • Transcription Factors
  • Exosome Multienzyme Ribonuclease Complex
  • DIS3 protein, human