Smoking modifies pancreatic cancer risk loci on 2q21.3

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• Alternative Title:
  Cancer Res
• Personal Author:
  Mocci, Evelina ; Kundu, Prosenjit ; Wheeler, William ; Arslan, Alan A. ; Beane-Freeman, Laura E. ; Bracci, Paige M. ; Brennan, Paul ; Canzian, Federico ; Du, Mengmeng ; Gallinger, Steven ; Giles, Graham G. ; Goodman, Phyllis J. ; Kooperberg, Charles ; Le Marchand, Loic ; Neale, Rachel E. ; Shu, Xiao-Ou ; Visvanathan, Kala ; White, Emily ; Zheng, Wei ; Albanes, Demetrius ; Andreotti, Gabriella ; Babic, Ana ; Bamlet, William R. ; Berndt, Sonja I. ; Blackford, Amanda L. ; Bueno-de-Mesquita, Bas ; Buring, Julie E. ; Campa, Daniele ; Chanock, Stephen J. ; Childs, Erica J. ; Duell, Eric J. ; Fuchs, Charles S. ; Gaziano, J. Michael ; Giovannucci, Edward L. ; Goggins, Michael G. ; Hartge, Patricia ; Hassan, Manal M. ; Holly, Elizabeth A. ; Hoover, Robert N. ; Hung, Rayjean J. ; Kurtz, Robert C. ; Lee, I-Min ; Malats, Núria ; Milne, Roger L. ; Ng, Kimmie ; Oberg, Ann L. ; Panico, Salvatore ; Peters, Ulrike ; Porta, Miquel ; Rabe, Kari G. ; Riboli, Elio ; Rothman, Nathaniel ; Scelo, Ghislaine ; Sesso, Howard D. ; Silverman, Debra T. ; Stevens, Victoria L. ; Strobel, Oliver ; Thompson, Ian M. ; Tjonneland, Anne ; Trichopoulou, Antonia ; Van Den Eeden, Stephen K. ; Wactawski-Wende, Jean ; Wentzensen, Nicolas ; Wilkens, Lynne R. ; Yu, Herbert ; Yuan, Fangcheng ; Zeleniuch-Jacquotte, Anne ; Amundadottir, Laufey T. ; Li, Donghui ; Jacobs, Eric J. ; Petersen, Gloria M. ; Wolpin, Brian M. ; Risch, Harvey A. ; Kraft, Peter ; Chatterjee, Nilanjan ; Klein, Alison P. ; Stolzenberg-Solomon, Rachael
• Description:
  Germline variation and smoking are independently associated with pancreatic ductal adenocarcinoma (PDAC). We conducted genome-wide smoking interaction analysis of PDAC using genotype data from four previous genome-wide association studies in individuals of European ancestry (7,937 cases and 11,774 controls). Examination of expression quantitative trait loci data from the Genotype-Tissue Expression Project followed by colocalization analysis was conducted to determine whether there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and | < 5 × 10| was considered statistically significant. Genome-wide significant evidence of qualitative interaction was identified on chr2q21.3 in intron 5 of the transmembrane protein 163 (TMEM163) and upstream of the cyclin T2 (CCNT2). The most significant SNP using the Empirical Bayes method, in this region that included 45 significantly associated SNPs, was rs1818613 [per allele OR in never smokers 0.87, 95% confidence interval (CI), 0.82-0.93; former smokers 1.00, 95% CI, 0.91-1.07; current smokers 1.25, 95% CI 1.12-1.40, | | = 3.08 × 10|). Examination of the Genotype-Tissue Expression Project data demonstrated an expression quantitative trait locus in this region for TMEM163 and CCNT2 in several tissue types. Colocalization analysis supported a shared SNP, rs842357, in high linkage disequilibrium with rs1818613 (| | = 0. 94) driving both the observed interaction and the expression quantitative trait loci signals. Future studies are needed to confirm and understand the differential biologic mechanisms by smoking status that contribute to our PDAC findings. SIGNIFICANCE: This large genome-wide interaction study identifies a susceptibility locus on 2q21.3 that significantly modified PDAC risk by smoking status, providing insight into smoking-associated PDAC, with implications for prevention.
• Subjects:
  Carcinoma, Pancreatic Ductal Chromosomes, Human, Pair 2 Cyclin T Genetic Predisposition To Disease Genome-Wide Association Study Genotype Humans Membrane Proteins Pancreatic Neoplasms Polymorphism, Single Nucleotide Quantitative Trait Loci Risk Factors Smoking

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• Keywords:
  Epidemiology Genetics Interaction Pancreatic Cancer Smoking
• Source:
  Cancer Res. 81(11):3134-3143
• Pubmed ID:
  33574088
• Pubmed Central ID:
  PMC8178175
• Document Type:
  Journal Article
• Funding:
  R01 CA102765/CA/NCI NIH HHSUnited States/ ; P30 CA016087/CA/NCI NIH HHSUnited States/ ; R01 HL043851/HL/NHLBI NIH HHSUnited States/ ; R01 HL034595/HL/NHLBI NIH HHSUnited States/ ; UM1 CA182934/CA/NCI NIH HHSUnited States/ ; P30 ES000260/ES/NIEHS NIH HHSUnited States/ ; P50 CA102701/CA/NCI NIH HHSUnited States/ ; R01 HL026490/HL/NHLBI NIH HHSUnited States/ ; R01 CA154823/CA/NCI NIH HHSUnited States/ ; U58 DP003862/DP/NCCDPHP CDC HHSUnited States/ ; HHSN261200800001C/RC/CCR NIH HHSUnited States/ ; U01 CA247283/CA/NCI NIH HHSUnited States/ ; U10 CA037429/CA/NCI NIH HHSUnited States/ ; HHSN268201600002C/HL/NHLBI NIH HHSUnited States/ ; U01 CA182883/CA/NCI NIH HHSUnited States/ ; R01 HG010480/HG/NHGRI NIH HHSUnited States/ ; P01 CA087969/CA/NCI NIH HHSUnited States/ ; P50 CA062924/CA/NCI NIH HHSUnited States/ ; HHSN268201600018C/HL/NHLBI NIH HHSUnited States/ ; U01 CA182934/CA/NCI NIH HHSUnited States/ ; UG1 CA189974/CA/NCI NIH HHSUnited States/ ; ZIA CP010193/ImNIH/Intramural NIH HHSUnited States/ ; UM1 CA173640/CA/NCI NIH HHSUnited States/ ; R01 CA098870/CA/NCI NIH HHSUnited States/ ; P30 CA008748/CA/NCI NIH HHSUnited States/ ; HHSN268201600003C/HL/NHLBI NIH HHSUnited States/ ; Z99 CA999999/ImNIH/Intramural NIH HHSUnited States/ ; R01 CA098661/CA/NCI NIH HHSUnited States/ ; UM1 CA186107/CA/NCI NIH HHSUnited States/ ; P30 CA015083/CA/NCI NIH HHSUnited States/ ; HHSN268201600004C/HL/NHLBI NIH HHSUnited States/ ; UM1 CA182913/CA/NCI NIH HHSUnited States/ ; R01 CA047988/CA/NCI NIH HHSUnited States/ ; R01 CA109767/CA/NCI NIH HHSUnited States/ ; HHSN268201600001C/HL/NHLBI NIH HHSUnited States/ ; R01 HL080467/HL/NHLBI NIH HHSUnited States/ ; UM1 CA167552/CA/NCI NIH HHSUnited States/ ; U01 CA182913/CA/NCI NIH HHSUnited States/ ; R01 CA049449/CA/NCI NIH HHSUnited States/ ; R01 CA040360/CA/NCI NIH HHSUnited States/ ; 001/WHO_/World Health OrganizationInternational/ ; UM1 CA182910/CA/NCI NIH HHSUnited States/ ; R01 CA097075/CA/NCI NIH HHSUnited States/ ; RC1 HL099355/HL/NHLBI NIH HHSUnited States/ ; UM1 CA182883/CA/NCI NIH HHSUnited States/ ; R01 CA097193/CA/NCI NIH HHSUnited States/ ; R01 CA034944/CA/NCI NIH HHSUnited States/ ; HHSN261200800001E/CA/NCI NIH HHSUnited States/ ; R03 CA123546/CA/NCI NIH HHSUnited States/
• Volume:
  81
• Issue:
  11
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:0e6507aa59b118a2ac8bdbba52599d59f4d5a7f3dba91fc37b9be2f5c8f5bd92
• Download URL:
  https://stacks.cdc.gov/view/cdc/112129/cdc_112129_DS1.pdf
• File Type:
  [PDF - 718.94 KB ]