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Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer

  • Rosenberger, Albert1, 2
  • Muttray, Nils1
  • Hung, Rayjean J.3, 4
  • Christiani, David C.5
  • Caporaso, Neil E.6
  • Liu, Geoffrey7, 3
  • Bojesen, Stig E.8, 9, 10
  • Le Marchand, Loic11
  • Albanes, Demetrios6
  • Aldrich, Melinda C.12
  • Tardon, Adonina13
  • Fernández-Tardón, Guillermo13
  • Rennert, Gad14
  • Field, John K.15
  • Davies, Michael P. A.15
  • Liloglou, Triantafillos15
  • Kiemeney, Lambertus A.16
  • Lazarus, Philip17
  • Wendel, Bernadette1
  • Haugen, Aage18
  • And 20 more
  • 1 Georg-August-University Göttingen, Göttingen, Germany , Göttingen (Germany)
  • 2 Universitätsmedizin Göttingen, Humboldtallee 32, Göttingen, 37073, Germany , Göttingen (Germany)
  • 3 University of Toronto, Toronto, ON, Canada , Toronto (Canada)
  • 4 University of Toronto, Toronto, Canada , Toronto (Canada)
  • 5 Harvard T.H. Chan School of Public Health and Massachusetts General Hospital/Harvard Medical School, Boston, MA, USA , Boston (United States)
  • 6 National Cancer Institute, US National Institutes of Health, Bethesda, MD, USA , Bethesda (United States)
  • 7 Princess Margaret Cancer Centre, Toronto, ON, Canada , Toronto (Canada)
  • 8 Copenhagen University Hospital, Copenhagen, Denmark , Copenhagen (Denmark)
  • 9 University of Copenhagen, Copenhagen, Denmark , Copenhagen (Denmark)
  • 10 Herlev and Gentofte Hospital, Copenhagen, Denmark , Copenhagen (Denmark)
  • 11 University of Hawaii Cancer Center, Honolulu, HI, USA , Honolulu (United States)
  • 12 Vanderbilt University Medical Center, Nashville, TN, USA , Nashville (United States)
  • 13 University of Oviedo, ISPA and CIBERESP, Oviedo, Spain , Oviedo (Spain)
  • 14 Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel , Haifa (Israel)
  • 15 Roy Castle Lung Cancer Research Programme, The University of Liverpool, Liverpool, UK , Liverpool (United Kingdom)
  • 16 Radboud University Medical Center, Nijmegen, The Netherlands , Nijmegen (Netherlands)
  • 17 Washington State University, Spokane, WA, USA , Spokane (United States)
  • 18 National Institute of Occupational Health, Oslo, Norway , Oslo (Norway)
  • 19 British Columbia Cancer Agency, Vancouver, BC, Canada , Vancouver (Canada)
  • 20 H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA , Tampa (United States)
  • 21 Geisel School of Medicine, Hanover, NH, USA , Hanover (United States)
  • 22 Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain , Barcelona (Spain)
  • 23 University of Kentucky, Lexington, KY, USA , Lexington (United States)
  • 24 Swedish Medical Group, Seattle, WA, USA , Seattle (United States)
  • 25 Fred Hutchinson Cancer Research Center, Seattle, WA, USA , Seattle (United States)
  • 26 University of Utah, Salt Lake City, UT, USA , Salt Lake City (United States)
  • 27 University of Sheffield, Sheffield, UK , Sheffield (United Kingdom)
  • 28 University of Salzburg and Cancer Cluster Salzburg, Salzburg, Austria , Salzburg (Austria)
  • 29 Translational Lung Research Center (TLRC) Heidelberg, Heidelberg, Germany , Heidelberg (Germany)
  • 30 Thoraxklinik, University Hospital Heidelberg, Heidelberg, Germany , Heidelberg (Germany)
  • 31 Umeå University, Umeå, Sweden , Umeå (Sweden)
  • 32 International Agency for Research on Cancer, World Health Organization, Lyon, France , Lyon (France)
  • 33 The University of Texas MD Anderson Cancer Center, Houston, TX, USA , Houston (United States)
  • 34 Baylor College of Medicine, Houston, TX, USA , Houston (United States)
Published Article
European Journal of Medical Research
BioMed Central
Publication Date
Jan 31, 2022
DOI: 10.1186/s40001-022-00638-7
Springer Nature
  • Research


BackgroundAberrant Wnt signalling, regulating cell development and stemness, influences the development of many cancer types. The Aryl hydrocarbon receptor (AhR) mediates tumorigenesis of environmental pollutants. Complex interaction patterns of genes assigned to AhR/Wnt-signalling were recently associated with lung cancer susceptibility.AimTo assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent.MethodsOdds ratios (OR) were estimated for genomic variants assigned to the Wnt agonist and the antagonistic genes DKK2, DKK3, DKK4, FRZB, SFRP4 and Axin2. Logistic regression models with variable selection were trained, validated and tested to predict lung cancer, at which other previously identified SNPs that have been robustly associated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate variant × variant interaction. All analyses were performed for overall lung cancer and for subgroups.ResultsNo genome-wide significant association of AhR/Wnt-genes with overall lung cancer was observed, but within the subgroups of ever smokers (e.g., maker rs2722278 SFRP4; OR = 1.20; 95% CI 1.13–1.27; p = 5.6 × 10–10) and never smokers (e.g., maker rs1133683 Axin2; OR = 1.27; 95% CI 1.19–1.35; p = 1.0 × 10–12). Although predictability is poor, AhR/Wnt-variants are unexpectedly overrepresented in optimized prediction scores for overall lung cancer and for small cell lung cancer. Remarkably, the score for never-smokers contained solely two AhR/Wnt-variants. The optimal decision tree for never smokers consists of 7 AhR/Wnt-variants and only two lung cancer variants.ConclusionsThe role of variants belonging to Wnt/AhR-pathways in lung cancer susceptibility may be underrated in main-effects association analysis. Complex interaction patterns in individuals of European descent have moderate predictive capacity for lung cancer or subgroups thereof, especially in never smokers.

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