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

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

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)66328-66343
Number of pages16
JournalOncotarget
Volume7
Issue number41
DOIs
StatePublished - 2016

Keywords

  • Fine-mapping
  • GWAS
  • Imputation
  • NR5A2
  • Pancreatic cancer

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