Association of the 15q25 and 5p15 Lung Cancer Susceptibility Regions with Gene Expression in Lung Tumor Tissue

Background: Genome-wide association studies have identified two independent lung cancer susceptibility loci at chromosome 15q25 and one locus at 5p15. We examined the association of genetic variants in these regions with gene expression in lung tumor tissue, in an effort to elucidate carcinogenic mechanisms by which these variants influence lung cancer risk. Methods: We used data from 2 independent studies of non-small cell lung carcinoma patients: the JBR.10 clinical trial (n = 131) and a University Health Network (UHN) patient sample in Toronto (n = 181). We genotyped seven 15(125 and five 5p15 variants and examined their association with expression profiles of genes in the corresponding regions, measured by Affymetrix HG-U133A. Results: The minor allele (C) of a variant representing one of the two loci at 15q25 (rs2036534) was associated with increased iron-responsive element binding protein 2 (IREB2) expression in both studies (JBR.10 P = 0.042; UHN P = 0.002). A false discovery rate of 0.05 or less in the UHN sample increased our confidence in this association. The association appears to be more prominent among lung adenocarcinoma patients. We did not detect an association between genotype and expression profile for the other 15q25 locus or for 5p15 variants. Conclusions: In contrast to previous studies that indicate 15q25 variants are associated with lung cancer risk through an effect on smoking behavior, our results suggest these variants may influence risk through a second mechanism, involving modulation of IREB2 expression. Impact: This finding expands on potential mechanisms through which 15q25 variants influence lung cancer risk and may have implications for future research on chemoprevention strategies. Cancer Epidemiol Biomarkers Prev; 21(7); 1097-104. (C)2012 AACR.