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Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

ABSTRACT: 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.

SUBMITTER: Zhang M 

PROVIDER: S-EPMC5340084 | biostudies-literature | 2016 Oct

REPOSITORIES: biostudies-literature

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Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21.

Zhang Mingfeng M   Wang Zhaoming Z   Obazee Ofure O   Jia Jinping J   Childs Erica J EJ   Hoskins Jason J   Figlioli Gisella G   Mocci Evelina E   Collins Irene I   Chung Charles C CC   Hautman Christopher C   Arslan Alan A AA   Beane-Freeman Laura L   Bracci Paige M PM   Buring Julie J   Duell Eric J EJ   Gallinger Steven S   Giles Graham G GG   Goodman Gary E GE   Goodman Phyllis J PJ   Kamineni Aruna A   Kolonel Laurence N LN   Kulke Matthew H MH   Malats Núria N   Olson Sara H SH   Sesso Howard D HD   Visvanathan Kala K   White Emily E   Zheng Wei W   Abnet Christian C CC   Albanes Demetrius D   Andreotti Gabriella G   Brais Lauren L   Bueno-de-Mesquita H Bas HB   Basso Daniela D   Berndt Sonja I SI   Boutron-Ruault Marie-Christine MC   Bijlsma Maarten F MF   Brenner Hermann H   Burdette Laurie L   Campa Daniele D   Caporaso Neil E NE   Capurso Gabriele G   Cavestro Giulia Martina GM   Cotterchio Michelle M   Costello Eithne E   Elena Joanne J   Boggi Ugo U   Gaziano J Michael JM   Gazouli Maria M   Giovannucci Edward L EL   Goggins Michael M   Gross Myron M   Haiman Christopher A CA   Hassan Manal M   Helzlsouer Kathy J KJ   Hu Nan N   Hunter David J DJ   Iskierka-Jazdzewska Elzbieta E   Jenab Mazda M   Kaaks Rudolf R   Key Timothy J TJ   Khaw Kay-Tee KT   Klein Eric A EA   Kogevinas Manolis M   Krogh Vittorio V   Kupcinskas Juozas J   Kurtz Robert C RC   Landi Maria T MT   Landi Stefano S   Le Marchand Loic L   Mambrini Andrea A   Mannisto Satu S   Milne Roger L RL   Neale Rachel E RE   Oberg Ann L AL   Panico Salvatore S   Patel Alpa V AV   Peeters Petra H M PH   Peters Ulrike U   Pezzilli Raffaele R   Porta Miquel M   Purdue Mark M   Quiros J Ramón JR   Riboli Elio E   Rothman Nathaniel N   Scarpa Aldo A   Scelo Ghislaine G   Shu Xiao-Ou XO   Silverman Debra T DT   Soucek Pavel P   Strobel Oliver O   Sund Malin M   Małecka-Panas Ewa E   Taylor Philip R PR   Tavano Francesca F   Travis Ruth C RC   Thornquist Mark M   Tjønneland Anne A   Tobias Geoffrey S GS   Trichopoulos Dimitrios D   Vashist Yogesh Y   Vodicka Pavel P   Wactawski-Wende Jean J   Wentzensen Nicolas N   Yu Herbert H   Yu Kai K   Zeleniuch-Jacquotte Anne A   Kooperberg Charles C   Risch Harvey A HA   Jacobs Eric J EJ   Li Donghui D   Fuchs Charles C   Hoover Robert R   Hartge Patricia P   Chanock Stephen J SJ   Petersen Gloria M GM   Stolzenberg-Solomon Rachael S RS   Wolpin Brian M BM   Kraft Peter P   Klein Alison P AP   Canzian Federico F   Amundadottir Laufey T LT  

Oncotarget 20161001 41

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 additiona  ...[more]

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