Inherited variation at chromosome 12p13.33, including RAD52, influences the risk of squamous cell lung carcinoma

Abstract

Although lung cancer is largely caused by tobacco smoking, inherited genetic factors play a role in its etiology. Genome-wide association studies in Europeans have only robustly demonstrated 3 polymorphic variations that influence the risk of lung cancer. Tumor heterogeneity may have hampered the detection of association signal when all lung cancer subtypes were analyzed together. In a genome-wide association study of 5,355 European ever-smoker lung cancer patients and 4,344 smoking control subjects, we conducted a pathway-based analysis in lung cancer histologic subtypes with 19,082 single-nucleotide polymorphisms mapping to 917 genes in the HuGE-defined "inflammation" pathway. We identified a susceptibility locus for squamous cell lung carcinoma at 12p13.33 (RAD52, rs6489769) and replicated the association in 3 independent studies totaling 3,359 squamous cell lung carcinoma cases and 9,100 controls (OR = 1.20, P(combined) = 2.3 × 10(-8)).

Significance: The combination of pathway-based approaches and information on disease-specific subtypes can improve the identification of cancer susceptibility loci in heterogeneous diseases.

FIGURE 1. Pathway-level associations in the NCI GWAS by histology and smoking status

Current, former, ever smokers are identified. AD=adenocarcinoma; SQ=squamous cell carcinoma; SC=small cell carcinoma. Labeled are the analyses statistically significant after Bonferroni correction with two-sided P <0.05/12 = 0.004. For SQ and all subjects’ pathway analyses, the stronger statistical association in the combined former and current smoker sample suggests that there is a consistent effect of the SNPs across the smoking groups.

FIGURE 2. Discovery of 12p13.33 as a susceptibility locus for squamous cell carcinoma of the lung

Upper panel: Manhattan plot of P-values from the inflammation pathway gene SNPs in the NCI SQ discovery data. The green line corresponds to the Bonferroni threshold of p=2.6×10⁻⁶ for the 19,082 SNPs included in the pathway analysis. Lower panel: Regional plot of the 12p13.33 SQ susceptibility locus. Plot shows association results of genotyped (diamonds) and imputed (circles) SNPs, along with recombination rates (light blue lines) estimated from the HapMap CEU samples. SNPs are colored based on their LD with rs6489769. The size of the diamonds indicates the strength of association. Genes in the region are annotated with locations and orientations using the UCSC genome browser.