European Journal of Medical Research (Jan 2022)
Gene–gene interaction of AhRwith and within the Wntcascade affects susceptibility to lung cancer
- Albert Rosenberger,
- Nils Muttray,
- Rayjean J. Hung,
- David C. Christiani,
- Neil E. Caporaso,
- Geoffrey Liu,
- Stig E. Bojesen,
- Loic Le Marchand,
- Demetrios Albanes,
- Melinda C. Aldrich,
- Adonina Tardon,
- Guillermo Fernández-Tardón,
- Gad Rennert,
- John K. Field,
- Michael P. A. Davies,
- Triantafillos Liloglou,
- Lambertus A. Kiemeney,
- Philip Lazarus,
- Bernadette Wendel,
- Aage Haugen,
- Shanbeh Zienolddiny,
- Stephen Lam,
- Matthew B. Schabath,
- Angeline S. Andrew,
- Eric J. Duell,
- Susanne M. Arnold,
- Gary E. Goodman,
- Chu Chen,
- Jennifer A. Doherty,
- Fiona Taylor,
- Angela Cox,
- Penella J. Woll,
- Angela Risch,
- Thomas R. Muley,
- Mikael Johansson,
- Paul Brennan,
- Maria Teresa Landi,
- Sanjay S. Shete,
- Christopher I. Amos,
- Heike Bickeböller,
- The INTEGRAL-ILCCO Consortium
Affiliations
- Albert Rosenberger
- Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen
- Nils Muttray
- Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen
- Rayjean J. Hung
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, University of Toronto
- David C. Christiani
- Department of Environmental Health, Harvard T.H. Chan School of Public Health and Massachusetts General Hospital/Harvard Medical School
- Neil E. Caporaso
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health
- Geoffrey Liu
- Medical Oncology and Medical Biophysics, Princess Margaret Cancer Centre
- Stig E. Bojesen
- Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital
- Loic Le Marchand
- Epidemiology Program, University of Hawaii Cancer Center
- Demetrios Albanes
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health
- Melinda C. Aldrich
- Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center
- Adonina Tardon
- Faculty of Medicine, University of Oviedo, ISPA and CIBERESP
- Guillermo Fernández-Tardón
- Faculty of Medicine, University of Oviedo, ISPA and CIBERESP
- Gad Rennert
- Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine
- John K. Field
- Department of Molecular and Clinical Cancer Medicine, Roy Castle Lung Cancer Research Programme, The University of Liverpool
- Michael P. A. Davies
- Department of Molecular and Clinical Cancer Medicine, Roy Castle Lung Cancer Research Programme, The University of Liverpool
- Triantafillos Liloglou
- Department of Molecular and Clinical Cancer Medicine, Roy Castle Lung Cancer Research Programme, The University of Liverpool
- Lambertus A. Kiemeney
- Departments of Health Evidence and Urology, Radboud University Medical Center
- Philip Lazarus
- Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University
- Bernadette Wendel
- Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen
- Aage Haugen
- National Institute of Occupational Health
- Shanbeh Zienolddiny
- National Institute of Occupational Health
- Stephen Lam
- British Columbia Cancer Agency
- Matthew B. Schabath
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute
- Angeline S. Andrew
- Department of Epidemiology, Geisel School of Medicine
- Eric J. Duell
- Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program, Catalan Institute of Oncology (ICO), Bellvitge Biomedical Research Institute (IDIBELL)
- Susanne M. Arnold
- Markey Cancer Center, University of Kentucky
- Gary E. Goodman
- Swedish Medical Group
- Chu Chen
- Program in Epidemiology, Fred Hutchinson Cancer Research Center
- Jennifer A. Doherty
- Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah
- Fiona Taylor
- Department of Oncology and Metabolism, University of Sheffield
- Angela Cox
- Department of Oncology and Metabolism, University of Sheffield
- Penella J. Woll
- Department of Oncology and Metabolism, University of Sheffield
- Angela Risch
- University of Salzburg and Cancer Cluster Salzburg
- Thomas R. Muley
- Member of the German Center for Lung Research (DZL), Translational Lung Research Center (TLRC) Heidelberg
- Mikael Johansson
- Department of Radiation Sciences, Umeå University
- Paul Brennan
- International Agency for Research on Cancer, World Health Organization
- Maria Teresa Landi
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health
- Sanjay S. Shete
- Department of Biostatistics, Division of Basic Sciences, The University of Texas MD Anderson Cancer Center
- Christopher I. Amos
- Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine
- Heike Bickeböller
- Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen
- The INTEGRAL-ILCCO Consortium
- DOI
- https://doi.org/10.1186/s40001-022-00638-7
- Journal volume & issue
-
Vol. 27,
no. 1
pp. 1 – 13
Abstract
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.
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