A genome-wide association study of lung cancer identifies a region of chromosome 5p15 associated with risk for adenocarcinoma

Abstract

Three genetic loci for lung cancer risk have been identified by genome-wide association studies (GWAS), but inherited susceptibility to specific histologic types of lung cancer is not well established. We conducted a GWAS of lung cancer and its major histologic types, genotyping 515,922 single-nucleotide polymorphisms (SNPs) in 5739 lung cancer cases and 5848 controls from one population-based case-control study and three cohort studies. Results were combined with summary data from ten additional studies, for a total of 13,300 cases and 19,666 controls of European descent. Four studies also provided histology data for replication, resulting in 3333 adenocarcinomas (AD), 2589 squamous cell carcinomas (SQ), and 1418 small cell carcinomas (SC). In analyses by histology, rs2736100 (TERT), on chromosome 5p15.33, was associated with risk of adenocarcinoma (odds ratio [OR]=1.23, 95% confidence interval [CI]=1.13-1.33, p=3.02x10(-7)), but not with other histologic types (OR=1.01, p=0.84 and OR=1.00, p=0.93 for SQ and SC, respectively). This finding was confirmed in each replication study and overall meta-analysis (OR=1.24, 95% CI=1.17-1.31, p=3.74x10(-14) for AD; OR=0.99, p=0.69 and OR=0.97, p=0.48 for SQ and SC, respectively). Other previously reported association signals on 15q25 and 6p21 were also refined, but no additional loci reached genome-wide significance. In conclusion, a lung cancer GWAS identified a distinct hereditary contribution to adenocarcinoma.

Figure 1

“Manhattan Plot” of Meta-Analysis Results for Lung Cancer Susceptibility Loci Genome-wide association results for 13,300 primary lung cancer cases and 19,666 controls. −Log₁₀ p values plotted against the chromosomal positions are depicted. “Set 1 SNPs” includes the core of 279,698 SNPs that were available across all studies. “Set 2 SNPs” includes 197,647 SNPs that were available only for a subset of the studies that used HumanHap500 or denser genomic platforms or provided summary data on imputed SNPs. The plot has been truncated at p < 10⁻¹⁰. There were 37 additional SNPs with lower p values, which are included in the list of the top 200 SNPs reported in Table S5.

Figure 2

Results of Association Analyses and LD Block for the 5p15.33 Locus by Histology Association results are shown in the top panel for the NCI GWAS. Results of the meta-analysis combining the NCI GWAS and the additional four studies for rs2736100 in the adenocarcinoma histologic type are indicated by the purple diamond. Red circles indicate adenocarcinoma, blue triangles indicate squamous cell carcinoma, and green circles indicate small cell carcinoma. At the bottom, pairwise LD is depicted for 65 SNPs with minor allele frequency >5% in the 5p15.33 region extending from 1204161 to 1496199. The LD among pairs of SNPs was characterized on the basis of the square of the correlation coefficient (r²) with the use of EAGLE and PLCO controls of a European background (1997 from EAGLE and 859 from PLCO, totaling 2856 unrelated individuals). Regions with high r² values are red, and regions with low r² values are light yellow. The shade lightens with decreasing r². The purple bar indicates the approximate location of the TERT gene.

Figure 3

Forest Plot Showing Associations between the rs2736100 SNP and Lung Cancer Risk Both Overall and by Histologic Types Left panel: (A) Association between rs2736100 and lung cancer risk in each study included in the NCI GWAS and in each additional study contributing to the meta-analysis. Right panel: (B) Association between rs2736100 and risk of adenocarcinoma, (C) squamous cell carcinoma, and (D) small cell carcinoma in the NCI GWAS and in each additional study contributing to the meta-analysis, stratified by histology. Individual studies (boxes) are plotted against the individual effect sizes (ORs). The size of the boxes is inversely proportioned to the variance. Horizontal lines indicate 95% CIs. The dashed vertical line in each panel shows the value for no effect (OR =1.0).

Figure 4

Location of SNPs and Mutations in the TERT Gene Exon and intron organization of the TERT gene, including the locations of rs2736100, rs2853676, and the known mutations (red asterisks) that compromise telomerase activity.