Gene-gene interaction of <i>AhR</i>with and within the <i>Wnt</i>cascade affects susceptibility to lung cancer

Rosenberger, Albert, Muttray, Nils, Hung, Rayjean J, Christiani, David C, Caporaso, Neil E, Liu, Geoffrey, Bojesen, Stig E, Le Marchand, Loic, Albanes, Demetrios, Aldrich, Melinda C
et al (show 30 more authors) (2022) Gene-gene interaction of <i>AhR</i>with and within the <i>Wnt</i>cascade affects susceptibility to lung cancer. EUROPEAN JOURNAL OF MEDICAL RESEARCH, 27 (1). 14-.

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<h4>Background</h4>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.<h4>Aim</h4>To assess the association and predictive ability of AhR/Wnt-genes with lung cancer in cases and controls of European descent.<h4>Methods</h4>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.<h4>Results</h4>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<sup>-10</sup>) and never smokers (e.g., maker rs1133683 Axin2; OR  = 1.27; 95% CI 1.19-1.35; p  = 1.0 × 10<sup>-12</sup>). 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.<h4>Conclusions</h4>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.

Item Type: Article
Uncontrolled Keywords: Susceptibility, Association, Gene-gene integration, Prediction, Polygenic risk score, Decision trees, Never smoker, Small cell lung cancer
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 13 Jan 2022 16:00
Last Modified: 18 Oct 2023 09:47
DOI: 10.1186/s40001-022-00638-7
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