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About this Publication
Title
Smoking modifies pancreatic cancer risk loci on 2q21.3.
Pubmed ID
33574088 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Cancer Res. 2021 Feb 11
Authors
Mocci E, Kundu P, Wheeler W, Arslan AA, Beane-Freeman LE, Bracci PM, Brennan P, Canzian F, Du M, Gallinger S, Giles GG, Goodman PJ, Kooperberg C, Le Marchand L, Neale RE, Shu XO, Visvanathan K, White E, Zheng W, Albanes D, Andreotti G, ...show more Babic A, Bamlet WR, Berndt SI, Blackford AL, Bueno-de-Mesquita B, Buring JE, Campa D, Chanock SJ, Childs EJ, Duell EJ, Fuchs CS, Gaziano JM, Giovannucci EL, Goggins MG, Hartge P, Hassan MM, Holly EA, Hoover RN, Hung RJ, Kurtz RC, Lee IM, Malats N, Milne RL, Ng K, Oberg AL, Panico S, Peters U, Porta M, Rabe KG, Riboli E, Rothman N, Scelo G, Sesso HD, Silverman DT, Stevens VL, Strobel O, Thompson IM, Tjonneland A, Trichopoulou A, Van Den Eeden SK, Wactawski-Wende J, Wentzensen N, Wilkens LR, Yu H, Yuan F, Zeleniuch-Jacquotte A, Amundadottir LT, Li D, Jacobs EJ, Petersen GM, Wolpin BM, Risch HA, Kraft P, Chatterjee N, Klein AP, Stolzenberg-Solomon R
Affiliations
  • Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
  • Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
  • Information Management Services, Inc., Silver Spring, Maryland.
  • Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York.
  • Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.
  • Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
  • International Agency for Research on Cancer, Lyon, France.
  • Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Lunenfeld-Tanenbaum Research Institute, Sinai Health System and University of Toronto, Toronto, Ontario, Canada.
  • Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
...show more
  • SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii.
  • Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Australia.
  • Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee.
  • Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, Washington.
  • Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota.
  • Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands.
  • Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
  • Department of Biology, University of Pisa, Pisa, Italy.
  • Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain.
  • Yale Cancer Center, New Haven, Connecticut.
  • Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts.
  • Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland.
  • Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas.
  • Gastroenterology, Hepatology, and Nutrition Service, Memorial Sloan Kettering Cancer Center, New York, New York.
  • Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre, Madrid, Spain.
  • Department of Clinical Medicine and Surgery, Federico II University, Naples, Italy.
  • CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain.
  • Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom.
  • Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
  • Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.
  • CHRISTUS Santa Rosa Hospital - Medical Center, San Antonio, Texas.
  • Department of Public Health, University of Copenhagen and Danish Cancer Society Research Center Diet, Genes and Environment, Copenhagen, Denmark.
  • Hellenic Health Foundation, World Health Organization Collaborating Center of Nutrition, Medical School, University of Athens, Greece.
  • Division of Research, Kaiser Permanente Northern California, Oakland, California.
  • Department of Epidemiology and Environmental Health, University of Buffalo, Buffalo, New York.
  • Department of Population Health, New York University School of Medicine, New York, New York.
  • Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut.
  • Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland. rs221z@nih.gov aklein1@jhmi.edu.
  • Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland. rs221z@nih.gov aklein1@jhmi.edu.
Abstract

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 if there was support for common SNP(s) underlying the observed associations. Statistical tests were two sided and P-values < 5 x 10-8 were 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 which included 45 significantly associated SNPs, was rs1818613 (per allele OR in never smokers 0.87, 95% 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, interaction P-value=3.08x10-9). 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 LD with rs1818613 (r2=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.

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