Abstract
Recent genome-wide association studies (GWASs) have identified 15q25.1 as a lung cancer susceptibility locus. Here, we sought to explore the direct carcinogenic effects of genetic variants in this region on the risk of developing lung adenocarcinoma (ADC). Five common SNPs (rs8034191, rs16969968, rs1051730, rs938682, and rs8042374) spanning the 15q25.1 locus were assayed in a case-control study examining a cohort of 301 lung ADCs and 318 healthy controls. Stratification analysis by gender, smoking status, and tumor, node, metastasis (TNM) classification, was performed. In addition, sections from ADC tissue and normal tissue adjacent to tumors were stained with an anti-CHRNA3 (cholinergic receptor nicotinic α3) antibody by immunohistochemistry in 81 cases. Our results demonstrate that rs8042374, a variant of the CHRNA3 gene, is associated with an increased risk of ADC with an OR of 1.76 (95% CI: 1.17–2.65, p = 0.024). This variant was linked to a greater risk of ADC in female nonsmokers (OR (95% CI): 1.81 (1.05–3.12), p = 0.032) and female stage I + II cases (OR (95% CI): 1.92 (1.03–3.57), p = 0.039). Although located within the same gene, rs938682 showed protective effects for smokers, stage III + IV cases, and male stage III + IV cases. Additionally, the CHRNA3 protein level in ADC tissue was slightly higher than in the surrounding normal lung tissue, based on immunohistochemical analysis. Our results suggest that the CHRNA3 polymorphism functions as a genetic modifier of the risk of developing lung ADC in the Chinese population, particularly in nonsmoking females.
Highlights
Primary lung cancer is the most common cancer, responsible for over one million deaths worldwide annually [1]
ADC risk was found for heterozygotes (GA) of rs8042374G/A in the CHRNA3 gene, with an odds ratio (OR) = 1.76 (95% confidence interval (CI), 1.17–2.65; p = 0.024) in the codominant model, as well as a more highly significant association in the overdominant model as the fitting model with an OR = 1.71 compared with the genotypes (GG/AA) (Table 2)
Our results demonstrate that rs8034191, rs16969968 and rs1051730, variants in AGPHD1, CHRNA5 and CHRNA3, respectively, display non-significant associations with ADC
Summary
Primary lung cancer is the most common cancer, responsible for over one million deaths worldwide annually [1]. Single-nucleotide polymorphisms (SNPs) are the most common and stable markers of human genetic variation, and may be associated with the risk of a variety of cancers, including that of the lung [3,4]. Much evidence of a direct/indirect effect of polymorphic variation at 15q25.1 on lung cancer risk has been provided by genome-wide association studies (GWASs) and segregation analyses in European, American and Asian populations [5,6,7,8]. Three SNPs (rs8034191, rs1051730 and rs16969968) at 15q25.1 were consistently strongly associated with lung cancer risk in both smokers and nonsmokers in populations of European descent [5,8]
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