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.

Different Effects of <i>TERT</i>, <i>TP</i>63, and <i>CYP</i>2<i>A</i>6 Polymorphism on Individual Risk of Tobacco-Related Lung Cancer in Male Japanese Smokers

“…Data reported by Wang et al [16], demonstrating that TERT-CLPTM1L variants showed the strongest association for adenocarcinoma and weak but similar trend for squamous cell carcinoma in never-smokers, supported our preset results. On the other hand, CHARN3-CHRAN5 also located on 15q25 has been reported one of the most import factors identified in GWAS in Caucasian populations [7,9]; however, the association of these variants were not replicated in this study ( Table 1). The cause of these differences was probably because of their extremely low frequency in the Asian population, as has been reported by other Japanese group [17].…”

“…Further analysis will be interested to clarify the cancer type-specific effects of TP63 polymorphism. An important contribution of TERT on 5p15 variants to lung cancer has been suggested by multiple research groups [7,10,16]. The rs2736100 in TERT were significantly associated with lung cancer risk (p = 0.00504), as shown in Table 1.…”

“…Recent GWAS have identified lung cancer susceptibility genes such as TERT [7,9], CLPTM1L, CHRNA3-CHR-NA5, and TP63 [10]. We performed a replication study of these associations in a population of male Japanese smokers (a total of 1,460 subjects), which were previously studied for lung cancer risk [12].…”

“…Among several reports from genome-wide association studies (GWAS), nicotinic cholinergic receptor α (CHRNA3-CHRNA5, rs1051730 or rs667282) has been identified as a lung cancer susceptible locus [6][7][8]. Similarly, recent GWAS with respect to lung cancer risk in different ethnic populations have suggested a variety of susceptible genes, such as telomerase reverse transcriptase (TERT, rs2736100) [7,9,10], cleft lip and palate transmembrane protein 1-like (CLPTM1L, rs401681) [6,11], HLA-B associated transcript-3 (BAT3, rs3117582) [6], and mutS homolog 5 (MSH5, rs3131379) [6]. Tumor protein p63 (TP63, rs4488809, rs9816619, or rs10937405) was newly identified as a susceptible gene for lung adenocarcinomas in the Japanese and Korean from GWAS [10].…”

Correlation of CLPTM1L polymorphisms with lung cancer susceptibility and response to cisplatin-based chemotherapy in a Chinese Han population

“…Candidate tagging SNPs (tSNPs) in CLPTM1L gene were selected from previously established polymorphisms associated with lung cancer or other cancers [10,13,18,[21][22][23]. Validated SNPs were selected with a minor allele frequency (MAF) >5 % in the HapMap Chinese Han Beijing (CHB) population.…”