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

Jason W. Hoskins, Abdisamad Ibrahim, Mickey A. Emmanuel, Sarah M. Manmiller, Yinglun Wu, Maura O'Neill, Jinping Jia, Irene Collins, Mingfeng Zhang, Janelle V. Thomas, Lauren M. Rost, Sudipto Das, Hemang Parikh, Jefferson M. Haake, Gail L. Matters, Robert C. Kurtz, William R. Bamlet, Alison Klein, Rachael Stolzenberg-Solomon, Brian M. WolpinRonit Yarden, Zhaoming Wang, Jill Smith, Sara H. Olson, Thorkell Andresson, Gloria M Petersen, Laufey T. Amundadottir

Research output: Contribution to journalArticle

8 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)4726-4738
Number of pages13
JournalHuman Molecular Genetics
Volume25
Issue number21
DOIs
StatePublished - 2016

Fingerprint

Pancreatic Neoplasms
Alleles
TCF Transcription Factors
Nuclear RNA
Exosome Multienzyme Ribonuclease Complex
Wnt Signaling Pathway
Genome-Wide Association Study
RNA Stability
Protein Binding
Radioactivity
Genes
Single Nucleotide Polymorphism
Catalytic Domain
Chromosomes
Genome
Population
Neoplasms

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Hoskins, J. W., Ibrahim, A., Emmanuel, M. A., Manmiller, S. M., Wu, Y., O'Neill, M., ... Amundadottir, L. T. (2016). Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression. Human Molecular Genetics, 25(21), 4726-4738. https://doi.org/10.1093/hmg/ddw300

Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression. / Hoskins, Jason W.; Ibrahim, Abdisamad; Emmanuel, Mickey A.; Manmiller, Sarah M.; Wu, Yinglun; O'Neill, Maura; Jia, Jinping; Collins, Irene; Zhang, Mingfeng; Thomas, Janelle V.; Rost, Lauren M.; Das, Sudipto; Parikh, Hemang; Haake, Jefferson M.; Matters, Gail L.; Kurtz, Robert C.; Bamlet, William R.; Klein, Alison; Stolzenberg-Solomon, Rachael; Wolpin, Brian M.; Yarden, Ronit; Wang, Zhaoming; Smith, Jill; Olson, Sara H.; Andresson, Thorkell; Petersen, Gloria M; Amundadottir, Laufey T.

In: Human Molecular Genetics, Vol. 25, No. 21, 2016, p. 4726-4738.

Research output: Contribution to journalArticle

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, Yarden, R, Wang, Z, Smith, J, Olson, SH, Andresson, T, Petersen, GM & Amundadottir, LT 2016, 'Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression', Human Molecular Genetics, vol. 25, no. 21, pp. 4726-4738. https://doi.org/10.1093/hmg/ddw300
Hoskins, Jason W. ; Ibrahim, Abdisamad ; Emmanuel, Mickey A. ; Manmiller, Sarah M. ; Wu, Yinglun ; O'Neill, Maura ; Jia, Jinping ; Collins, Irene ; Zhang, Mingfeng ; Thomas, Janelle V. ; Rost, Lauren M. ; Das, Sudipto ; Parikh, Hemang ; Haake, Jefferson M. ; Matters, Gail L. ; Kurtz, Robert C. ; Bamlet, William R. ; Klein, Alison ; Stolzenberg-Solomon, Rachael ; Wolpin, Brian M. ; Yarden, Ronit ; Wang, Zhaoming ; Smith, Jill ; Olson, Sara H. ; Andresson, Thorkell ; Petersen, Gloria M ; Amundadottir, Laufey T. / Functional characterization of a chr13q22.1 pancreatic cancer risk locus reveals long-range interaction and allele-specific effects on DIS3 expression. In: Human Molecular Genetics. 2016 ; Vol. 25, No. 21. pp. 4726-4738.
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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.",
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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.

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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