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Title: Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21
Authors: Zhang, Mingfeng
Wang, Zhaoming
Obazee, Ofure
Jia, Jinping
Childs, Erica J
Hoskins, Jason
Figlioli, Gisella
Mocci, Evelina
Collins, Irene
Chung, Charles C
Hautman, Christopher
Arslan, Alan A
Beane-Freeman, Laura
Bracci, Paige M
Buring, Julie
Duell, Eric J
Gallinger, Steven
Giles, Graham G
Goodman, Gary E
Goodman, Phyllis J
Kamineni, Aruna
Kolonel, Laurence N
Kulke, Matthew H
Malats, Núria
Olson, Sara H
Sesso, Howard D
Visvanathan, Kala
White, Emily
Zheng, Wei
Abnet, Christian C
Albanes, Demetrius
Andreotti, Gabriella
Brais, Lauren
Bueno-de-Mesquita, H Bas
Basso, Daniela
Berndt, Sonja I
Boutron-Ruault, Marie-Christine
Bijlsma, Maarten F
Brenner, Hermann
Burdette, Laurie
Campa, Daniele
Caporaso, Neil E
Capurso, Gabriele
Cavestro, Giulia Martina
Cotterchio, Michelle
Costello, Eithne
Elena, Joanne
Boggi, Ugo
Gaziano, J Michael
Gazouli, Maria
Giovannucci, Edward L
Goggins, Michael
Gross, Myron
Haiman, Christopher A
Hassan, Manal
Helzlsouer, Kathy J
Hu, Nan
Hunter, David J
Iskierka-Jazdzewska, Elzbieta
Jenab, Mazda
Kaaks, Rudolf
Key, Timothy J
Khaw, Kay-Tee
Klein, Eric A
Kogevinas, Manolis
Krogh, Vittorio
Kupcinskas, Juozas
Kurtz, Robert C
Landi, Maria T
Landi, Stefano
Le Marchand, Loic
Mambrini, Andrea
Mannisto, Satu
Milne, Roger L
Neale, Rachel E
Oberg, Ann L
Panico, Salvatore
Patel, Alpa V
Peeters, Petra H M
Peters, Ulrike
Pezzilli, Raffaele
Porta, Miquel
Purdue, Mark
Quiros, J Ramón
Riboli, Elio
Rothman, Nathaniel
Scarpa, Aldo 
Scelo, Ghislaine
Shu, Xiao-Ou
Silverman, Debra T
Soucek, Pavel
Strobel, Oliver
Sund, Malin
Małecka-Panas, Ewa
Taylor, Philip R
Tavano, Francesca
Travis, Ruth C
Thornquist, Mark
Tjønneland, Anne
Tobias, Geoffrey S
Trichopoulos, Dimitrios
Vashist, Yogesh
Vodicka, Pavel
Wactawski-Wende, Jean
Wentzensen, Nicolas
Yu, Herbert
Yu, Kai
Zeleniuch-Jacquotte, Anne
Kooperberg, Charles
Risch, Harvey A
Jacobs, Eric J
Li, Donghui
Fuchs, Charles
Hoover, Robert
Hartge, Patricia
Chanock, Stephen J
Petersen, Gloria M
Stolzenberg-Solomon, Rachael S
Wolpin, Brian M
Kraft, Peter
Klein, Alison P
Canzian, Federico
Amundadottir, Laufey T
Keywords: GWAS;NR5A2;fine-mapping;imputation;pancreatic cancer
Mesh headings: Chromosomes, Human, Pair 1;Chromosomes, Human, Pair 5;Chromosomes, Human, Pair 8;Genetic Predisposition to Disease;Pancreatic Neoplasms
Secondary Mesh headings: Datasets as Topic;Genome-Wide Association Study;Genotype;Humans;Polymorphism, Single Nucleotide
Issue Date: 11-Oct-2016
Journal: Oncotarget 
Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.
DOI: 10.18632/oncotarget.11041
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