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

European Journal of Medical Research

The INTEGRAL-ILCCO Consortium¹  Stephen Lam²  Gad Rennert³  Christopher I. Amos⁴  Sanjay S. Shete⁵  Matthew B. Schabath⁶  Stig E. Bojesen⁷  David C. Christiani⁸  Angeline S. Andrew⁹  Nils Muttray^1,10  Bernadette Wendel^1,10  Albert Rosenberger^1,10  Heike Bickeböller^1,10  Michael P. A. Davies^1,11  Triantafillos Liloglou^1,11  John K. Field^1,11  Fiona Taylor^1,12  Angela Cox^1,12  Penella J. Woll^1,12  Philip Lazarus^1,13  Jennifer A. Doherty^1,14  Mikael Johansson^1,15  Melinda C. Aldrich^1,16  Lambertus A. Kiemeney^1,17  Neil E. Caporaso^1,18  Demetrios Albanes^1,18  Maria Teresa Landi^1,18  Loic Le Marchand^1,19  Guillermo Fernández-Tardón^2,20  Adonina Tardon^2,20  Paul Brennan^2,21  Rayjean J. Hung^2,22  Susanne M. Arnold^2,23  Geoffrey Liu^2,24  Thomas R. Muley^2,25  Aage Haugen^2,26  Shanbeh Zienolddiny^2,26  Chu Chen^2,27  Gary E. Goodman^2,28  Eric J. Duell^2,29  Angela Risch^3,30 

[1]

[2]British Columbia Cancer Agency

[3]Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine

[4]Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine

[5]Department of Biostatistics, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center

[6]Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute

[7]Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital

[8]Department of Environmental Health, Harvard T.H. Chan School of Public Health and Massachusetts General Hospital/Harvard Medical School

[9]Department of Epidemiology, Geisel School of Medicine

[10]Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen

[11]Department of Molecular and Clinical Cancer Medicine, Roy Castle Lung Cancer Research Programme, The University of Liverpool

[12]Department of Oncology and Metabolism, University of Sheffield

[13]Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University

[14]Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah

[15]Department of Radiation Sciences, Umeå University

[16]Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center

[17]Departments of Health Evidence and Urology, Radboud University Medical Center

[18]Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health

[19]Epidemiology Program, University of Hawaii Cancer Center

[20]Faculty of Medicine, University of Oviedo, ISPA and CIBERESP

[21]International Agency for Research on Cancer, World Health Organization

[22]Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto

[23]Markey Cancer Center, University of Kentucky

[24]Medical Oncology and Medical Biophysics, Princess Margaret Cancer Centre

[25]Member of the German Center for Lung Research (DZL), Translational Lung Research Center (TLRC) Heidelberg

[26]National Institute of Occupational Health

[27]Program in Epidemiology, Fred Hutchinson Cancer Research Center

[28]Swedish Medical Group

[29]Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL)

[30]University of Salzburg and Cancer Cluster Salzburg

关键词: Susceptibility;    Association;    Gene–gene integration;    Prediction;    Polygenic risk score;    Decision trees;   

DOI  :  10.1186/s40001-022-00638-7

来源: DOAJ

【 摘 要 】

Abstract Background Aberrant 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. Aim To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent. Methods Odds 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. Results No 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. Conclusions The 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.

【 授权许可】

Unknown