Citations 2
A Transcriptome-Wide Association Study Identifies Novel Candidate Susceptibility Genes for Pancreatic Cancer
Zhong, Jun, Jermusyk, Ashley , Wu, Lang , Hoskins, Jason W. , Collins, Irene , Mocci, Evelina , Song, Lei , Chung, Charles C., Xiao, Wenming , Andreotti, Gabriella , Arslan, Alan A. , Babić, Ana , Berndt, Sonja, Borgida, Ayelet , Bracci, Paige M. , Brennan, Paul , Bueno‐de‐Mesquita, Bas , Buring, Julie E. , Childs, Erica J., Du, Mengmeng , Fuchs, Charles S. , Gallinger, Steven , Gaziano, J. Michael, Giovannucci, Edward L. , Goodman, Gary E. , Goodman, Phyllis J. , Haiman, Christopher, Hartge, Patricia, Hasan, Manal , Helzlsouer, Kathy J., Holly, Elizabeth A., Klein, Eric A. , Kogevinas, Manolis, Kurtz, Robert J., Ng, Kimmie , Obazee, Ofure , Oberg, Ann L. , Patel, Alpa V. , Peters, Ulrike , Porta, Miquel , Rothman, Nathaniel , Scélo, Ghislaine , Sesso, Howard D. , Sieri, Sabina , Tjønneland, Anne , Thornquist, Mark, Trichopoulou, Antonia , Visvanathan, Kala , Wactawski‐Wende, Jean , Wentzensen, Nicolas , Yuan, Chen , Zeleniuch‐Jacquotte, Anne , Hoover, Robert N. , Brown, Kevin M. , Jacobs, Eric J. , Li, Donghui , Yu, Kai , Wolpin, Brian M. , Chatterjee, Nilanjan , Shi, Jianxin , Petersen, Gloria M. , Zhong, Jun , Arslan, Alan A , Tjønneland, Anne , Wactawski-Wende, Jean , Visvanathan, Kala , Klein, Eric A , Porta, Miquel , Zeleniuch-Jacquotte, Anne , Zhong, Jun , Yuan, Chen , Hoskins, Jason W , Zhang, Mingfeng , Zhang, Tongwu , Albanes, Demetrius , Bamlet, William R. , Freeman, Laura E. Beane , Brais, Lauren K , Canzian, Federico , Cotterchio, Michelle , Duell, Eric J. , Giles, Graham G. , Goggins, Michael , Marchand, Loı̈c Le , Malats, Núria , Männistö, Satu , Milne, Roger L. , Neale, Rachel Ε. , Orlow, Irene , Rothman, Nathaniel , Severi, Gianluca , Silverman, Debra T. , Sund, Malin , Tobias, Geoffrey S. , Van Den Eeden, Stephen K , White, Emily , Yu, Kai , Kooperberg, Charles , Risch, Harvey A. , Shu, Xiao‐Ou , Chanock, Stephen Jacob , Stolzenberg‐Solomon, Rachael Z. , Klein, Alison P. , Smith, Jill Palmer , Kraft, Peter , Zheng, Wei , Ámundadóttir, Laufey T.
JNCI: Journal of the National Cancer Institute | December 31, 2019 | Volume: 112 | Issue: 10 | Pages: 1003-1012
Abstract Background Although 20 pancreatic cancer susceptibility loci have been identified through genome-wide association studies in individuals of European ancestry, much of its heritability remains unexplained and the genes responsible largely unknown. Methods To discover novel pancreatic cancer risk loci and possible causal genes, we performed a pancreatic cancer transcriptome-wide association study in Europeans using three approaches: FUSION, MetaXcan, and Summary-MulTiXcan. We integrated genome-wide association studies summary statistics from 9040 pancreatic cancer cases and 12 496 controls, with gene expression prediction models built using transcriptome data from histologically normal pancreatic tissue samples (NCI Laboratory of Translational Genomics [n = 95] and Genotype-Tissue Expression v7 [n = 174] datasets) and data from 48 different tissues (Genotype-Tissue Expression v7, n = 74–421 samples). Results We identified 25 genes whose genetically predicted expression was statistically significantly associated with pancreatic cancer risk (false discovery rate < .05), including 14 candidate genes at 11 novel loci (1p36.12: CELA3B; 9q31.1: SMC2, SMC2-AS1; 10q23.31: RP11-80H5.9; 12q13.13: SMUG1; 14q32.33: BTBD6; 15q23: HEXA; 15q26.1: RCCD1; 17q12: PNMT, CDK12, PGAP3; 17q22: SUPT4H1; 18q11.22: RP11-888D10.3; and 19p13.11: PGPEP1) and 11 at six known risk loci (5p15.33: TERT, CLPTM1L, ZDHHC11B; 7p14.1: INHBA; 9q34.2: ABO; 13q12.2: PDX1; 13q22.1: KLF5; and 16q23.1: WDR59, CFDP1, BCAR1, TMEM170A). The association for 12 of these genes (CELA3B, SMC2, and PNMT at novel risk loci and TERT, CLPTM1L, INHBA, ABO, PDX1, KLF5, WDR59, CFDP1, and BCAR1 at known loci) remained statistically significant after Bonferroni correction. Conclusions By integrating gene expression and genotype data, we identified novel pancreatic cancer risk loci and candidate functional genes that warrant further investigation.
Abstract 1442: Analysis of cis-eQTLs in normal and tumor-derived pancreatic tissues reveals functional insights, including for the 9q34.1 ABO pancreatic cancer risk locus
Andresen, Soren Lykke, Xiao, Wenming , Jermusyk, Ashley , Rost, Lauren M., Collins, Irene , Jia, Jinping , Mobaraki, Michael, Zhu, Bin , Kurtz, Robert J., Song, Lei , Chatterjee, Nilanjan , Brian, Wolpin, Petersen, Gloria, Shi, Jianxin , Ámundadóttir, Laufey T. , Hoskins, Jason W. , Jia, Jinping, Mobaraki, Michael, Parikh, Hemang M. , Yeager, Meredith , Jensen, Torben Heick , Bamlet, William R. , Smith, Jill Palmer , Olson, Sara H. , Zhang, Mingfeng
Cancer Research | July 31, 2017 | Volume: 77 | Issue: 13_Supplement | Pages: 1442-1442
Abstract Objective: To elucidate the genetic architecture of gene expression in pancreatic tissues. Design: We performed expression quantitative trait locus (eQTL) and allele specific expression (ASE) analyses using RNA-sequence data and 1000 Genomes (1000G) imputed GWAS genotypes from 95 fresh frozen histologically normal pancreatic tissue samples. Data from 115 pancreatic tumor-derived tissue samples from The Cancer Genome Atlas (TCGA) was included for comparison. Results: We identified 38,615 cis-eQTLs (corresponding to 484 Genes) in histologically normal tissues and 39,713 cis-eQTL (corresponding to 237 Genes) in tumor tissues (FDR<0.1), with the strongest effects seen near transcriptional start sites (TSS). Approximately 23% and 42% of genes with significant cis-eQTLs (eGenes) appeared to be specific for tumor and normal derived tissues, respectively. Significant enrichment of cis-eQTL variants was noted in noncoding regulatory regions marked by modified histones, DNAse hypersensitivity and bound transcription factors, in particular for pancreatic tissues (1.53-3.12 fold, P≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 in the ABO gene (rs687289) was associated with ABO expression in histologically normal (P=5.8x10-8) and tumor-derived (P=8.3x10-5) pancreatic tissues. The high linkage disequilibrium (LD) between this variant and the O blood group generating deletion variant in exon 6 of ABO suggested that nonsense-mediated decay (NMD) of the “O” mRNA could explain the eQTL. However, knock-down of crucial NMD regulators did not influence decay of the ABO “O” mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL. Conclusions: We have identified cis-eQTLs representing potential functional regulatory variants in the pancreas and generated a rich dataset for further studies on gene expression and regulation in pancreatic tissues. Citation Format: Laufey T. Amundadottir, Soren Lykke Andresen, Wenming Xiao, Jason Hoskins, Ashley Jermusyk, Lauren Rost, Irene Collins, Jinping Jia, Michael Mobaraki, Bin Zhu, Robert Kurtz, Hemang Parikh, Lei Song, Meredith Yeager, Torben Jensen, William Bamlet, Nilanjan Chatterjee, Brian Wolpin, Jill Smith, Sara Olson, Gloria Petersen, Jianxin Shi, Mingfeng Zhang. Analysis of cis-eQTLs in normal and tumor-derived pancreatic tissues reveals functional insights, including for the 9q34.1 ABO pancreatic cancer risk locus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1442. doi:10.1158/1538-7445.AM2017-1442