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

Background: Aberrant Wnt signalling, regulating cell development and stemness, infuences 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 antagonis‑ tic 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 identifed SNPs that have been robustly associ‑ ated with lung cancer risk could also enter the model. Furthermore, decision trees were created to investigate vari‑ ant × variant interaction. All analyses were performed for overall lung cancer and for subgroups. Results: No genome-wide signifcant 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...