Promoter-Specific Variants in NeuroD1 and H3K4me3 Coincident Regions and Clinical Outcomes of Small Cell Lung Cancer

Background@#Neurogenic differentiation 1 (NeuroD1) is a representative small cell lung cancer (SCLC) transcription regulator involved in the carcinogenesis and behavior of SCLC.Histone modifications play an important role in transcription, and H3 lysine 4 trimethylation (H3K4me3) is primarily associated with promoter regions. @*Methods@#We investigated the association between single nucleotide polymorphisms (SNPs) in NeuroD1 and H3K4me3 coincident regions, selected using ChIP sequencing (ChIP-seq), and the clinical outcomes of 261 patients with SCLC. @*Results@#Among 230 SNPs, two were significantly associated with both the chemotherapy response and overall survival (OS) of patients with SCLC. RNF145 rs2043268A>G was associated with worse chemotherapy response and OS (under a recessive model, adjusted odds ratio [aOR], 0.50, 95% confidence interval [CI], 0.26–0.94, P = 0.031, and adjusted hazard ratio [aHR], 1.88, 95% CI, 1.38–2.57, P G was also associated with worse chemotherapy response and OS (under a dominant model, aOR, 0.47, 95% CI, 0.23–0.99, P = 0.046, and aHR, 2.03, 95% CI, 1.47–2.82, P G and CINP rs762105A>G were associated with clinical outcomes in patients with SCLC and also affected the promoter activity of each gene.

The effect of susceptibility variants, identified in never-smoking female lung cancer cases, on male smokers

Background/Aims@#Genome wide and candidate gene association studies have identified polymorphisms associated with the risk of lung cancer in never-smokers. This study was conducted to evaluate the association between 11 polymorphisms identified in female never smokers and the lung cancer risk in male smokers. @*Methods@#This study included 714 lung cancer patients and 626 healthy controls. The polymorphisms were genotyped using SEQUENOM MassARRAY iPLEX assay or Taq-Man assay. @*Results@#Two polymorphisms were associated with the risk of lung cancer in male smokers, as in female never smokers. Male smokers carrying the rs4975616 variant allele had a significantly decreased risk of lung cancer (in a codominant model: odds ratio, 0.77; 95% confidence interval, 0.61 to 0.96; p = 0.02). The rs9387478 polymorphism also reduced lung cancer risk in male smokers (in a codominant model: odds ratio, 0.85; 95% confidence interval, 0.73 to 0.997; p = 0.046). In a stratified analysis, the association between these polymorphisms and the risk of lung cancer was predominant in lighter smokers and for cases of adenocarcinoma. @*Conclusions@#These results suggest that a subset of polymorphisms known to be associated with the risk of lung cancer in female never smokers is also associated with the risk of lung cancer in male smokers.

The Different Effect of VEGF Polymorphisms on the Prognosis of Non-Small Cell Lung Cancer according to Tumor Histology

Vascular endothelial growth factor (VEGF) contributes to tumor angiogenesis. The role of VEGF single nucleotide polymorphisms (SNPs) in lung cancer susceptibility and its prognosis remains inconclusive and controversial. This study was performed to investigate whether VEGF polymorphisms affect survival outcomes of patients with early stage non-small cell lung cancer (NSCLC) after surgery. Three potentially functional VEGF SNPs (rs833061T>C, rs2010963G>C, and rs3025039C>T) were genotyped. A total of 782 NSCLC patients who were treated with surgical resection were enrolled. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. In overall population, none of the three polymorphisms were significantly associated with OS or DFS. However, when the patients were stratified by tumor histology, squamous cell carcinoma (SCC) and adenocarcinoma (AC) had significantly different OS (Adjusted hazard ratio [aHR] = 0.76, 95% CI = 0.56–1.03 in SCC; aHR = 1.33, 95% CI = 0.98–1.82 in AC; P for heterogeneity = 0.01) and DFS (aHR = 0.75, 95% CI = 0.58–0.97 in SCC; aHR = 1.26, 95% CI = 1.00–1.60 in AC; P for heterogeneity = 0.004) according to the rs833061T>C genotypes. Our results suggest that the prognostic role of VEGF rs833061T>C may differ depending on tumor histology.

Telomerase Activity and the Risk of Lung Cancer

Telomerase play a key role in the maintenance of telomere length and chromosome integrity. We have evaluated the association between telomerase activity and the risk of lung cancer in peripheral blood. Telomerase activity in peripheral blood mononuclear cells was measured by a PCR-designed telomeric repeat amplification protocol in 63 lung cancer patients and 190 healthy controls that were matched for age, gender, and smoking status. Telomerase activity was significantly lower in the lung cancer patients than in controls (mean +/- standard deviation; 1.32 +/- 1.65 vs 2.60 +/- 3.09, P < 1 x 10(-4)). When telomerase activity was categorized into quartiles based on telomerase activity in the controls, the risk of lung cancer increased as telomerase activity reduced (Ptrend = 1 x 10(-4)). Moreover, when the subjects were categorized based on the median value of telomerase activity, subjects with low telomerase activity were at a significantly increased risk of lung cancer compared to subjects with high telomerase activity (adjusted odds ratio = 3.05, 95% confidence interval = 1.60-5.82, P = 7 x 10-4). These findings suggest that telomerase activity may affect telomere maintenance, thereby contributing to susceptibility to lung cancer.

EML4-ALK Fusion Gene in Korean Non-Small Cell Lung Cancer

A fusion gene between echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) has been identified in non-small cell lung cancers (NSCLCs). Although a few studies have evaluated EML4-ALK fusion genes in Korean NSCLCs, the prevalence of different EML4-ALK fusion variants has yet to be clearly assessed. Herein, we have examined the profiles of EML4-ALK fusion gene variants in Korean patients of NSCLCs. EML4-ALK fusion genes have been detected in 10 (6.0%) of 167 patients of NSCLCs and in 9 (7.4%) of 121 patients of adenocarcinoma. Of the 10 patients with fusion genes identified, 8 (80%) were E13;A20 (variant 1) and 2 (20%) were E6;A20, with an additional 33-bp sequence derived from intron 6 of EML4 (variant 3b). These results indicate that the profiles of EML4-ALK fusion gene variants in Korean patients of NSCLC may differ from those in other ethnic populations. Herein, we describe for the first time the profiles of EML4-ALK fusion variants of Korean patients with NSCLCs.

A Functional Polymorphism in the CHRNA3 Gene and Risk of Chronic Obstructive Pulmonary Disease in a Korean Population

A genome-wide association study has identified the 15q25 region as being associated with the risk of chronic obstructive pulmonary disease (COPD) in Caucasians. This study intended as a confirmatory assessment of this association in a Korean population. The rs6495309C > T polymorphism in the promoter of nicotinic acetylcholine receptor alpha subunit 3 (CHRNA3) gene was investigated in a case-control study that consisted of 406 patients with COPD and 394 healthy control subjects. The rs6495309 CT or TT genotype was associated with a significantly decreased risk of COPD when compared to the rs6495309 CC genotype (adjusted odds ratio = 0.69, 95% confidence interval = 0.50-0.95, P = 0.023). The effect of the rs6495309C > T on the risk of COPD was more evident in moderate to very severe COPD than in mild COPD under a dominant model for the variant T allele (P = 0.024 for homogeneity). The CHRNA3 rs6495309C > T polymorphism on chromosome 15q25 is associated with the risk of COPD in a Korean population.

Polymorphisms in Apoptosis-Related Genes and TP53 Mutations in Non-Small Cell Lung Cancer

Apoptosis plays an essential role in the elimination of mutated or transformed cells from the body. Therefore, polymorphisms of apoptosis-related genes may lead to an alteration in apoptotic capacity, thereby affecting the occurrence of TP53 mutations in lung cancer. We investigated the relationship between potentially functional polymorphisms of apoptosis-related genes and TP53 mutations in non-small cell lung cancer (NSCLC). Twenty-seven single nucleotide polymorphisms in 20 apoptosis-related genes were genotyped by a sequenome mass spectrometry-based genotyping assay in 173 NSCLCs and the associations with TP53 mutations in the entire coding exons (exons 2-11), including splicing sites of the gene, were analyzed. None of the 27 polymorphisms was significantly associated with the occurrence of TP53 mutations. This suggests that apoptosis-related genes may not play an important role in the occurrence of TP53 mutations in lung cancer.

SERPINE2 Polymorphisms and Chronic Obstructive Pulmonary Disease

A number of genome-wide linkage analyses have identified the 2q33.3-2q37.2 region as most likely to contain the genes that contribute to the susceptibility to chronic obstructive pulmonary disease (COPD). It was hypothesized that the SERPINE2 gene, which is one of the genes located at the 2q33.3-2q37.2 region, may act as a low-penetrance susceptibility gene for COPD. To test this hypothesis, the association of four SERPINE2 single nucleotide polymorphisms (SNPs; rs16865421A>G, rs7583463A>C, rs729631C>G, and rs6734100C>G) with the risk of COPD was investigated in a case-control study of 311 COPD patients and 386 controls. The SNP rs16865421 was associated with a significantly decreased risk of COPD in a dominant model for the polymorphic allele (adjusted odds ratio [OR]=0.66, 95% confidence interval [CI]=0.45-0.97, P=0.03). In haplotype analysis, the GACC haplotype carrying the polymorphic allele at the rs16865421 was associated with a significantly decreased risk of COPD when compared to the AACC haplotype (adjusted OR=0.58, 95% CI=0.38-0.89, P=0.01), and this effect was evident in younger individuals (adjusted OR=0.30, 95% CI=0.14-0.64, P=0.002). This study suggests that the SERPINE2 gene contributes to the susceptibility to COPD.