Programmed Death Ligand 2 Gene Polymorphisms Are Associated With Lung Adenocarcinoma Risk in Female Never-Smokers

Abstract

ObjectivesLung cancer in never-smokers is a distinct disease associated with a different genomic landscape, pathogenesis, risk factors, and immune checkpoint inhibitor responses compared to those observed in smokers. This study aimed to identify novel single nucleotide polymorphisms (SNPs) of programmed death-1 (encoded by PDCD1) and its ligands, programmed death ligand 1 (CD274) and 2 (PDCD1LG2), associated with lung cancer risk in never-smoking women.Materials and MethodsDuring September 2002 and July 2012, we enrolled never-smoking female patients with lung adenocarcinoma (LUAD) (n=1153) and healthy women (n=1022) from six tertiary hospitals in Taiwan. SNP data were obtained and analyzed from the genome-wide association study dataset and through an imputation method. The expression quantitative trait loci (eQTL) analysis was performed in both tumor and non-tumor tissues for the correlation between genetic expression and identified SNPs.ResultsA total of 12 PDCD1LG2 SNPs related to LUAD risk were identified in never-smoking women, including rs2381282, rs4742103, rs4237162, rs4742104, rs12237624, rs78096119, rs6476988, rs7857315, rs10975178, rs7854413, rs56001683, and rs7858319. Among them, six tagged PDCD1LG2 SNPs rs2381282, rs4742103, rs4237162, rs4742104, rs78096119, and rs56001683 were significantly associated with LUAD risk. Specifically, two PDCD1LG2 SNPs, rs12237624 and rs78096119, were associated with previous pulmonary tuberculosis infection in relation to LUAD susceptibility. Through an eQTL assay, we found that rs2381282 (p < 0.001), rs12237624 (p = 0.019), and rs78096119 (p = 0.019) were associated with the expression levels of programed death ligand 2.ConclusionsNovel SNPs of programed death ligand 2 associated with lung adenocarcinoma risk were identified. Among them, two SNPs were associated with pulmonary tuberculosis infection in relation to lung adenocarcinoma susceptibility. These SNPs may help to stratify high-risk populations of never-smokers during lung cancer screening.

The relationship between previous pulmonary tuberculosis and risk of lung cancer in the future

“…TB infection can aggravate chronic inflammation, which may not only weaken the innate and acquired immune responses, but may also be related to the abnormal expression of immune-associated genes [ 96 ]. Tuberculosis infection, chronic obstructive pulmonary disease (COPD), smoking and cooking fume exposure, are defined as chronic inflammation-associated environmental exposures, and the interaction between these exposure factors and single nucleotide polymorphisms (SNPs) in lung cancer susceptibility has also been highly valued by researchers [ 97 ]. In this study, tuberculosis infection was an environmental exposure related to the risk of lung adenocarcinoma in women who had never smoked.…”

“…A new SNP for PDCD1LG2 related to lung adenocarcinoma risk has been identified. Among them, two SNPs related to susceptibility to lung adenocarcinoma are related to tuberculosis infection [ 97 ]. Cao et al analyzed the expression levels and function of PD-1, PD-L1, and PD-L2 in antigen-specific T cells from Mycobacterium tuberculosis patients and spleen lymphocytes from wild type and PD-1 knockout mice, and Lewis mice injected with lung cancer cells.…”

Lung cancer in never smokers: Tumor immunology and challenges for immunotherapy

“…These characteristics may help explain why NSCLC adenocarcinomas in never smokers typically do not demonstrate durable responses with immune checkpoint blockade despite PD-L1 expression (smokers have a higher PD-L1 expression) ( 56 ). Interestingly, PD-L2 gene (PDCD1LG2) single nucleotide polymorphisms (SNPs) are associated with lung adenocarcinoma risk in female never-smokers, and 3 of these SNPs were negatively associated with PD-L2 expression in non-tumor tissue, but not in tumor tissue ( 57 ). Although PD-L1 expression has been shown to be associated with carcinogenesis, tumor differentiation and vascular invasion, the role of PD-L2 is still poorly explored.…”

“…Although PD-L1 expression has been shown to be associated with carcinogenesis, tumor differentiation and vascular invasion, the role of PD-L2 is still poorly explored. Mechanistically, at low antigen concentrations the interaction between PD-L2 and PD-1 inhibits strong B7-CD28 signals, while at high concentrations, the interaction between PD-L2 and PD-1 reduces cytokine production, but not T cell proliferation, but the correlation between these PDCD1LG2 SNPs and PD-L2 expression requires further investigation, which might provide further insight into the PD-1/PD-L2 axis in T cell function and lung carcinogenesis ( 57 ).…”

MiRNA and Potential Prognostic Value in Non-Smoking Females with Lung Adenocarcinoma by High-Throughput Sequencing

“…Smoking is a major risk factor for lung carcinogenesis 2 ; however, about a quarter of lung cancer cases are not related to smoking, and it is reported that more than half of female patients never smoke. 3 Furthermore, the number of LUAD in female never smokers is gradually increasing. 4 , 5 Non-smoking females with LUAD account for a unique disease entity, showing different pathogenesis, epidemiological characteristics and course of disease.…”