Risk Of Non-small Cell Lung Cancer Research Articles

Meta-analysis of the Association between RASSF1A Gene Promoter Methylation and Non-small Cell Lung Cancer

背景与目的肿瘤发生、发展过程中，抑癌基因启动子区域CpG岛异常甲基化起着重要的作用。已有研究显示RAS相关区域家族1A(Ras association domain family 1A, RASSF1A)基因，作为一个抑癌基因其启动子区域甲基化与非小细胞肺癌(non-small cell lung cancer, NSCLC)的发生发展密切相关。在NSCLC患者癌组织中RASSF1A基因启动子往往表现为异常高甲基化。本研究采用meta分析的方法探讨RASSF1A基因启动子甲基化与NSCLC发生之间的关系。方法通过检索Medline、EMBASE、CNKI和万方数据库，按照已拟定的纳入与剔除标准筛选收集公开发表的关于RASSF1A基因启动子甲基化与NSCLC相关性的研究。以比值比(odds ratio, OR)和95%置信区间(confidence interval, CI)为效应指标，分析RASSF1A基因启动子甲基化与NSCLC的关系。结果共有23篇文献纳入本研究，RASSF1A基因启动子甲基化率在NSCLC患者肺部组织和对照组中分别为41.50%(95%CI: 34%-49%)和5.58%(95%CI: 2%-9%)，meta分析显示肿瘤组织中的甲基化率高于对照组(OR=8.72, 95%CI:4.88-15.58, P < 0.05)；亚组分析显示:肿瘤组织中的甲基化频率高于血浆(OR=10.99, 95%CI:2.48-48.68)和正常对照组织(OR=8.74, 95%CI: 4.39-17.41)。结论NSCLC患者肺癌组织中RASSF1A基因启动子甲基化率高于对照组，组织中RASSF1A基因启动子甲基化率对肺癌的发生更具影响，RASSSF1A甲基化可能与肺癌的发生存在相关并可作为肺癌诊断的潜在标志物。

Evaluating the Association of Eight Polymorphisms with Cancer Susceptibility in a Han Chinese Population.

BackgroundThe identification of susceptibility genes for specific types of cancer can provide necessary information for the complete characterization of cancer syndromes. Eight single nucleotide polymorphisms (SNPs), rs465498, rs17728461, rs4488809, rs753955, rs13361707, rs9841504, rs2274223, and rs13042395, were reported by genome wide association studies (GWASs) to be closely related to the susceptibility of lung cancer (LC), gastric cancer (GC) or esophageal cancer (EC) in Han population from northern or southern China. However, Chinese Han people from different geographic areas may have different genetic backgrounds. This study aims to assess the genetic associations of the eight SNPs mentioned above with three cancers risk in a Han population from northwest China.MethodsA total of 186 cancer-free controls and 436 cases with non-small cell lung cancer (NSCLC) (159 cases), non-cardia GC (167 cases) or EC (110 cases) were enrolled in this study. Chi-square test and polytomous logistic regression analyses were used to estimate the association between eight cancer-related SNPs and three cancers in a Han Chinese population from northwest China. The logistic regression results were adjusted for confounding factors and Benjamini and Hochberg False Discovery Rate (FDR) method was used to adjust the multiple hypothesis tests. Association analyses by cigarette smoking or alcohol drinking status were analyzed by crossover analyses.ResultsOne of the eight SNPs, rs17728461 was associated with NSCLC susceptibility (in a heterozygous model, OR = 0.44, 95% CI = 0.27–0.72, p = 0.001). Two SNPs, rs753955 and rs13042395, were associated with the risk of non-cardia GC in different genetic models (p < 0.05). No SNPs were associated with EC. The crossover analyses showed that the rs13042395 CT genotype, combined with cigarette smoking or alcohol drinking, could further increase the risk for non-cardia GC (p < 0.05).ConclusionsThese results indicated that rs17728461 may be specifically associated with the risk of NSCLC. rs753955 and rs13042395 were specifically associated with susceptibility to non-cardia GC in Ningxia Han Chinese. Susceptibility-associated polymorphisms in the northwestern Han Chinese were not very consistent with those in the northern Han Chinese or southern Han Chinese. The validation of these findings with a functional evaluation and a larger population is still required.

Tankyrase 2 (TNKS2) polymorphism associated with risk in developing non-small cell lung cancer in a Chinese population

ObjectivesWe investigated the association between poly(ADP-ribose) polymerase Tankyrase 2 (TNKS2) single-nucleotide polymorphisms (SNPs) and the risk of developing non-small cell lung cancer (NSCLC) in a Han Chinese population. MethodsFive-hundred NSCLC cases and 500 healthy controls were genotyped for four TNKS2 tagging SNPs (rs1538833, rs1538833, rs1340420, and rs1340420). The association between genotype and NSCLC risk was evaluated by computing the odds ratio (OR) and 95% confidence interval (CI) using multivariate unconditional logistic regression analyses. ResultsIndividual alleles of the four TNKS2 SNPs were not associated with NSCLC risk in the studied Chinese population. However, patients carrying TNKS2 rs1340420 G/G and A/G genotypes were associated with a lower risk of developing NSCLC and adenocarcinoma (OR=0.14; 95% CI=0.02–1.15 and OR=0.11; 95% CI=0.03–0.91, respectively), whereas females patients homozygous for the TNKS2 rs1770474 T allele, a rare type, were associated with a higher risk of developing squamous-cell carcinoma (SCC) (OR=4.67; 95% CI=0.87–25.01). ConclusionTNKS2 rs1340420 SNP was associated with lower NSCLC risk, whereas rs1770474 SNP was associated with higher SCC risk, suggesting that these two SNPs may be useful predictors of risk of developing NSCLC and SCC in this Chinese population.

IL1B gene polymorphisms, age and the risk of non-small cell lung cancer in a Chinese population.

IL1B rs12621220G/A (-3893), rs1143623G/C (-1464), rs16944T/C (-511) and rs1143627C/T (-31) were previously reported to be associated with non-small cell lung cancer (NSCLC) and formed a specific haplotype (GGCT) which was associated with increased IL1B gene expression and increased risk of NSCLC in European populations. Only the two SNPs of rs16944T/C (-511) and rs1143627C/T (-31) have been studied in Chinese populations, and the results were conflicting. Thus we studied the association of the above four SNPs with NSCLC in a large Chinese population. We genotyped IL1B SNPs in a case-control study with 889 lung cancer cases and 1005 controls using the SNPscan Genotyping system. We used logistic regression to determine the association between each SNP and NSCLC estimated by ORs and their 95% confidence intervals (CIs), controlling for Potential confounders as appropriate. In subjects over age 63, significant associations were detected between NSCLC and IL1B SNPs. For rs12621220G>A (-3893) and rs1143623G>C (-1464), heterozygous variants, when compared with ancestral genotype, were significantly associated with decreased risk of NSCLC, with adjusted odds ratio (aOR)=0.710 (0.516, 0.976), P=0.035 and aOR=0.643 (0.466, 0.886), P=0.007, respectively. For rs16944T>C (-511) and rs1143627C>T (-31), homozygous variants were significantly associated with increased risk of NSCLC, with aOR=1.482 (1.084, 2.025), P=0.014 and aOR=1.450 (1.055, 1.994), P=0.022, respectively. Inference of the haplotype structures showed that rs12621220G/A (-3893), rs1143623G/C (-1464), rs16944T/C (-511) and rs1143627C/T (-31) formed two risk haplotypes (GGCC and ACTT) with linkage disequilibrium in all subjects, and they have significantly different frequencies between cases and controls after the permutation tests for one hundred thousand times (P=0.0000E0). Our study provided evidence that IL1B SNPs might be implicated in the pathogenesis of NSCLC in the Chinese population.

Association of p73 G4C14-to-A4T14 polymorphism with non-small cell lung cancer risk.

The p73 gene is a structural and functional homolog of the p53 gene, which has a crucial role in mediating cell cycle arrest and apoptosis. Numerous previous studies have investigated the polymorphism of p73 G4C14-to-A4T14 at exon 2, as it was suggested to affect gene expression and result in functional significance. However, the correlation of this polymorphism with clinicopathological variables of patients with non-small cell lung cancer (NSCLC) remains to be elucidated. The aim of the present study was to examine the association between the gene polymorphism of p73 G4C14-to-A4T14 and the risk of developing NSCLC. The single-nucleotide polymorphisms of p73 G4C14-to-A4T14 were genotyped using polymerase chain reaction with confronting two-pair primers and direct DNA sequencing in 186 NSCLC patients and 196 cancer-free controls. χ2-tests and logistic regression analysis were used to analyze the experimental data, including the determination of odds ratio (OR), 95% confidence intervals (95% CIs) and P-values. The results demonstrated that the AT/AT genotype was associated with a significantly decreased risk of NSCLC (P=0.010; OR=0.370; 95% CI=0.170-0.806) compared with the GC allele genotypes including GC/GC and GC/AT. In addition, carriers of the AT allele exhibited a significantly reduced risk of NSCLC (P=0.038; OR=0.713; 95% CI=0.517-0.983) compared with non-carriers. In conclusion, these results indicated that the p73 G4C14-to-A4T14 polymorphism was a potential marker of NSCLC genetic susceptibility. However, further studies with a larger population are required in order to confirm these results.

Clinicopathological significance and potential drug target of RUNX3 in non-small cell lung cancer: a meta-analysis.

BackgroundEmerging evidence indicates that RUNX3 is a candidate tumor suppressor in several types of human tumors, including non-small cell lung cancer (NSCLC). However, the correlation between RUNX3 hypermethylation and clinicopathological characteristics of NSCLC remains unclear. Here, we conducted a systematic review and meta-analysis to quantitatively evaluate the effects of RUNX3 hypermethylation on the incidence of NSCLC and clinicopathological characteristics.MethodsA detailed literature search was made using Medline, Embase and Web of Science for related research publications written in English. The methodological quality of the studies was evaluated. The data were extracted and assessed independently by two reviewers. Analysis of pooled data was performed. The odds ratio (OR) and hazard ratio were calculated and summarized.ResultsFinal analysis of 911 NSCLC patients from 13 eligible studies was performed. We observed that RUNX3 hypermethylation was significantly higher in NSCLC than in normal lung tissue; the pooled OR from seven studies including 361 NSCLC and 345 normal lung tissue (OR 7.08, confidence interval 4.12–12.17, P<0.00001). RUNX3 hypermethylation may also be associated with pathological types. The pooled OR was obtained from eleven studies including 271 squamous cell carcinoma and 389 adenocarcinoma (OR 0.41, confidence interval 0.19–0.89, P=0.02), which indicated that RUNX3 hypermethylation is significantly higher in adenocarcinoma that in squamous cell carcinoma. We did not find that RUNX3 hypermethylation was correlated with clinical stage or differentiated status. However, NSCLC patients with RUNX3 hypermethylation had a lower survival rate than those without RUNX3 hypermethylation.ConclusionThe results of this meta-analysis suggest that RUNX3 hypermethylation is associated with an increased risk and worse survival in NSCLC. RUNX3 hypermethylation, which induces inactivation of the RUNX3 gene, plays an important role in lung carcinogenesis and clinical outcome.

The association of adiponectin gene promoter variations with non-small cell lung cancer in a Han Chinese population.

Recently, in vitro studies have demonstrated that adiponectin has antiangiogenic and tumor growth-limiting properties. Additionally, serum adiponectin levels have been associated with the risk of several cancers; specifically, serum adiponectin was significantly lower in lung cancer patients with advanced-stage disease. In this study, we examined the association of adiponectin gene promoter variations associated with adiponectin gene expression and plasma levels in non-small cell lung cancer (NSCLC) in a Han Chinese population. A total of 319 patients with NSCLC and 489 healthy individuals were recruited to evaluate the association of four adiponectin gene promoter single-nucleotide polymorphisms (SNPs) (SNP-12140G>A, SNP-11426A>G, SNP-11391G>A and SNP-11377C>G) with NSCLS risk. Additionally, we constructed haplotypes of these four SNPs and evaluated the association of these haplotypes with NSCLS risk. Our results showed that among these four SNPs, only SNP-12140G>A was associated with NSCLC risk(P<0.05). The haplotype analysis showed that no haplotype was associated with NSCLC after performing a Bonferroni correction (P>0.05). Additionally, an association analysis of the four SNPs stratified into pathologic stages I+II and III+IV showed that these SNPs did not exhibit significant differences between pathologic stages I+II and III+IV. Moreover, we did not observe any differences in allele and genotype frequency for these SNPs between adenocarcinoma and squamous cell carcinoma. Our results indicated that the G allele of SNP-12140may be a risk factor for NSCLC (OR = 1.516; 95% CI: 1.098–2.094) in this Han Chinese population.

Genetic variations in DROSHA and DICER and survival of advanced non-small cell lung cancer: a two-stage study in Chinese population

MicroRNAs (miRNA) are a class of small, noncoding RNA molecules involved in carcinogenesis. Genetic variations in miRNA processing genes may affect the biogenesis of miRNAs, and consequently affect miRNAs regulation and development and progression of human cancer. Therefore, we hypothesized that polymorphisms in two main miRNA biosynthesis genes (DROSHA and DICER) may modulate the survival of advanced non-small cell lung cancer (NSCLC) patients in China. We selected 36 common tagging SNPs in DROSHA and DICER and evaluated the associations of these SNPs with survival of advanced NSCLC patients by a two-stage study in Chinese Han population (discovery cohort: 303 patients; replication cohort: 340 patients). Thirty-six SNPs were detected in the discovery cohort and 12 promising SNPs were validated in the replication cohort. The results showed that DROSHA rs3805525 was marginally associated with the survival of NSCLC patients in the replication cohort (dominant model: HR 0.69, 95 % CI 0.46–1.03, P = 0.071), which was in the same direction as that in the discovery cohort. When combing all patients into one group, three SNPs (rs3805525, rs17410035 and rs7719497) in DROSHA showed significantly associations with NSCLC survival (additive model: HR 0.82, 95 % CI 0.68–0.99 for rs3805525; HR 0.79, 95 % CI 0.62–1.00 for rs17410035; HR 0.76, 95 % CI 0.62–0.93 for rs7719497). Additionally, the combined analysis of those three SNPs showed a significant locus-dosage effect between number of favorable alleles and death risk of NSCLC (Trend P = 0.002). Genetic variations in DROSHA might be associated with the survival of advanced NSCLC patients in Chinese population.

Genetic polymorphisms and expression of HLA-G and its receptors, KIR2DL4 and LILRB1, in non-small cell lung cancer.

Human leukocyte antigen-G (HLA-G) is a nonclassical HLA class I molecule absent from most normal tissues but detected in many malignant tumors. It is recognized by cells of the immune system using LILRB1, KIR2DL4 and LILRB2 receptors. We attempted to find out whether some polymorphisms of HLA-G, LILRB1 and KIR2DL4 genes are associated with susceptibility to nonsmall cell lung cancer (NSCLC). Four polymorphisms in HLA-G, i.e. -964A>G (rs1632947), -725C>G>T (rs1233334), -716T>G (rs2249863) in the promoter, and a 14 base pair insertion/deletion (14 bp indel) in the 3'-untranslated region (3'UTR), and five in LILRB1-5651G>A (rs41308748) in intron 14, 5717C>T L622L (rs1061684), 5724G>A E625K (rs16985478), 5774 C>A P641P (rs41548213) in exon 15, and 5806C>T (rs8101240) in 3'UTR-as well as 9620 9A/10A (rs11410751) polymorphism in exon 7 of KIR2DL4 were typed using different laboratory techniques. Only one single nucleotide polymorphism (SNP) in HLA-G (-964A>G) and one in LILRB1 (5724G>A) were found to influence the risk of NSCLC. In addition, 5724G>A was associated with protection from tumor cell infiltration of regional lymph nodes. Most importantly, we detected HLA-G and LILRB1 expression in tumor specimens, but no correlation with genetic polymorphisms was observed. HLA-G and LILRB1 protein expression levels in tumor tissue were significantly correlated with tumor stage.

CCR2-64I polymorphism is associated with Non-Small Cell Lung Cancer in Tunisian patients

Single nucleotide polymorphism (SNPs) in genes coding for chemokines may be associated with some cancer. The purpose of this study was to investigate the impact of CCR2-64I and CXCL12-3′A SNPs on the susceptibility and the clinicopathological characteristics of NSCLC (Non-Small Cell Lung Cancer) in the Tunisian population. 170 NSCLC patients and 225 healthy controls screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis were enrolled. A significant association for the homozygous genotype CCR2 64I/64I with lung cancer risk was observed (P=0.004). An increased significant frequency of the -64I allele (P=0.0006) was noted in the patient’s group. Clinical analysis indicated a positive association of the -64I allele among squamous cell lung carcinoma patients (P=0.003). The CCR2 mRNA extracted from peripheral blood mononuclear cells (PBMC) was found highly expressed in NSCLC patients compared to controls. The same higher levels were found in patients carrying the CCR2 64I/64I genotype. No significant association was retrieved with CXCL12-3′A polymorphism. In conclusion, our results revealed that the subjects with -64I allele of CCR2-64I gene polymorphism, expressed a significantly higher risk for NSCLC risk without influence on its pathological progression.

Rs895819 within miR-27a might be involved in development of non small cell lung cancer in the Chinese Han population.

MicroRNA-27a (miR-27a) is deemed to be an oncogene that plays an important role in development of various cancers, and single nucleotide polymorphism (SNP) of miR-27a can influence the maturation or aberrant expression of hsa-miR27a, resulting in increased risk of cancer and poor prognosis for non-small cell lung cancer (NSCLC). This study aimed to assess the effects of rs895819 within miR-27a on susceptibility and prognosis of NSCLC patients in 560 clinical confirmed cases and 568 healthy check-up individuals. Adjusted odds/hazard ratios (ORs/HRs) and 95% confidential intervals (CIs) were calculated to evaluate the association between rs895819 and the risk and prognosis of NSCLC. The results showed that allele A and genotype GG of rs895819 were significantly associated with an increased risk of NSCLC (38.9% vs 30.8%, adjusted OR=1.26, 95%CI=1.23-1.29 for allele G vs A; 18.1% vs 11.7%, adjusted OR=1.67, 95%CI=1.59-1.75 for genotype GG vs AA). Moreover, positive associations were also observed in dominant and recessive models (53.7% vs 49.9%, adjusted OR=1.17, 95%CI=1.13-1.20 for GG/AG vs AA; 18.1% vs 11.7%, adjusted=1.65, 95%CI=1.58-1.73). However, no significant association was found between rs895819 and the prognosis of NSCLC in genotype, dominant and recessive models. These results suggested that miR-27a might be involved in NSCLC carcinogenesis, but not in progression of NSCLC. The allele G, genotype GG and allele G carrier (GG/AG vs AA) of rs895819 might be genetic susceptible factors for NSCLC. Further multi-central, large sample size and well-designed prospective studies as well as functional studies are warranted to verify our findings.

Association between a p73 gene polymorphism and genetic susceptibility to non-small cell lung cancer in the South of China.

This study aimed to identify any association between the p73 gene G4C14-to-A4T14 polymorphism and risk of non-small cell lung cancer (NSCLC) in the south of China. We genotyped the p73 gene polymorphism of peripheral blood DNA from 168 patients with NSCLC and 195 normal controls using HRM (high resolution melting) and PCR-CTPP (polymerase chain reaction with confronting two-pair primers). The results of genotyping by HRM and PCR-CTPP were consistent with direct sequencing, the p73 genotype distribution in 168 lung cancer patients being as follows: GC/GC 101 cases (60.1%), GC/ AT 59 cases (35.1%), AT/AT 8 cases (4.8%). The carriers of AT/AT genotype had a significantly reduced risk of NSCLC (OR=0.370; 95%CI: 0.170-0.806; p=0.010) as compared with non-carriers. However, we found no relations between p73 genotypes and histological type (p=0.798, x2=0.452), tumor stage (p=0.806, x2=0.806), or lymph node metastasis (p=0.578, x2=1.098). Our findings suggest that the p73 G4C14-to-A4T14 polymorphism may be a modifier of NSCLC susceptibility in the Chinese population.

TNF-β genetic variant contributes to the risk of non-small cell lung cancer

To investigate the association of TNF-β 252A >G variant with the risk of non-small cell lung cancer (NSCLC). Total 956 patients with NSCLC were recruited between January 2000 and December 2008 at Cancer Hospital, Chinese Academy of Medical Science as the case group, and 994 frequency-matched controls were randomly selected from a pool of cancer-free subjects recruited from a nutritional group. All the participants were unrelated Han Chinese. There were no age, gender restrictions. Smoking status of the subjects was surveyed. Informed consent was obtained and 3 ml peripheral blood was collected from each subject. All samples were genotyped by polymerase chain reaction-restriction fragment length polymorphism method (PCR-RFLP). The OR and 95%CI were estimated by logistic regression to evaluate the relationship between TNF-β 252 A/G variant and the risk of lung cancer. The frequencies of TNF-β 252 AA, AG and GG genotype were 30.9% (307/994) , 47.4% (471/994) and 21.7% (216/994) in lung cancer cases and 35.7% (341/956) , 48.1% (460/956) and 16.2% (155/956) in controls. Logistic regression analysis revealed that TNF-β 252 GG genotype contributed to a decreased risk of developing NSCLC (OR = 0.64, 95%CI: 0.49-0.83) compared with AA genotype. When stratified by smoking status, the individuals with 252 GG genotype had a significant increased risk of NSCLC (OR = 1.54, 95%CI:1.00-2.39) among smokers; which was less than those with AA genotype among smokers (OR = 2.88, 95%CI:1.91-2.24). When further stratified by smoking index, individuals with 252 GG genotype had a significant decreased risk of NSCLC among heavy smokers with OR (95%CI) of 2.24 (1.33-3.74), which was less than those with AA genotype (OR = 4.62, 95%CI:2.88-7.41). TNF-β genetic variant may interact with environment factor to contribute to the susceptibility to NSCLC.

Association of CD44 Gene Polymorphism with Survival of NSCLC and Risk of Bone Metastasis.

BackgroundPrevious studies have reported CD44 expression influenced the development and progression of tumors. The aim of this study was to investigate whether single-nucleotide polymorphisms (SNPs) of the CD44 gene are associated with survival of non-small cell lung cancer (NSCLC) and occurrence rate of bone metastasis.Material/MethodsA total of 234 patients with NSCLC between 2003 and 2010 were enrolled in this study and 468 healthy persons were used as controls. Two polymorphisms, rs13347 and rs187115, in the CD44 gene were genotyped using DNA from blood lymphocytes. For statistical analysis we used the chi-square test, Fisher’s exact test, Kaplan-Meier method, and log-rank test.ResultsCD44 gene rs13347 polymorphism was not associated with NSCLC risk. For rs187115, the association with NSCLC risk was observed (P<0.001). Allele G carriers had significantly higher occurrence rates of bone metastasis (OR=0.4, 95%CI: 0.20–0.64, P<0.001) and more advanced tumor stage (OR=2.6, 95%CI: 1.50–4.45, P=0.001) compared to carriers of allele A. The survival rates for patients with AA genotype were significantly higher than for patients with the AG+GG genotypes (P<0.001). In multivariate analysis of survival in NSCLC patients, significant predictors were CD44 gene (AG+GG) (RR=0.48, 95%CI: 0.34–0.68, P<0.001), tumor stage (RR=0.45, 95%CI: 0. 0.31–0.65, P<0.001), and bone metastasis (RR=1.52, 95%CI: 1.05–2.21, P=0.027).ConclusionsCD44 gene rs187115 polymorphism is a potential predictive marker of survival in NSCLC patients, and is significantly correlated with bone metastasis and tumor stage.

MiRNAs Associated Polymorphisms in the 3'UTR of MET Promote the Risk of Non-Small Cell Lung Cancer

Background/Aims: MET can act as an oncogene and its signaling server has essential roles in regulating tumorigenesis. Polymorphisms in MET have been reported to be associated with poor prognosis in human cancer, but an association with the risk of human non-small-cell lung cancer (NSCLC) has not been found so far. In this study rs41281081 and rs76322625, located in the 3'UTR of MET, were selected to evaluate their relationship with the risk of NSCLC among the Chinese population. Methods: A questionnaire, SNaPshot genotype assay, real time PCR assay, cell transfection and the dual luciferase reporter assay were used. Single-nucleotide polymorphisms (SNPs) of rs41281081 and rs76322625 in the 3' untranslated region (UTR) of MET was involved as a risk factor in the occurrence of NSCLC. Results: SNP rs41281081 could be regulated by miR-335 and rs76322625 could be regulated by miR-1026 to cause an up-regulation of MET in patients with NSCLC. Furthermore, the carriers of the GA and AA genotypes in rs41281081, and the CU and UU genotypes in rs76322625 presented with poor cell differentiation and large tumor size, as well as a high probability of metastasis. Conclusion: Our findings have shown that the SNPs rs41281081 and rs76322625 in MET 3ʹUTR, through disruption of the regulatory role of miR-335 and miR-1026 in MET expression, may act as promoting factors in the pathogenesis of NSCLC.

Relationship between genetic polymorphisms of DNA ligase 1 and non-small cell lung cancer susceptibility and radiosensitivity.

The aim of this study was to examine the relationship between genetic polymorphisms in DNA ligase 1 (LIG1) and non-small cell lung cancer (NSCLC) susceptibility and radiosensitivity in a Chinese population. This was a case-control study that included 352 NSCLC patients and 448 healthy controls. Polymerase chain reaction-restriction fragment length polymorphism analysis was conducted to detect HaeIII polymorphisms in exon 6 of the LIG1 gene in this popula-tion. This information was used to observe the effects of radiation in pa-tients with different genotypes in order to determine the genotypes as-sociated with radiosensitivity. The CC genotype and C allele frequency were significantly higher in the NSCLC group than in the control group (P = 0.012 and P = 0.023, respectively). The relative risk of experienc-ing NSCLC was 2.55 [95% confidence interval (CI), 1.12-3.98] for CC homozygous patients and 0.87 (95%CI, 0.46-1.88) for AA homozygous patients. Analysis of LIG1 genetic polymorphisms and radiosensitiv-ity of NSCLC patients showed that AA homozygous patients were sig-nificantly more radiosensitive than the control group (AA vs AC, P = 0.014; AA vs CC, P < 0.001; AC vs CC, P = 0.023). Therefore, the LIG1 CC genotype was associated with susceptibility to NSCLC, and the AA genotype demonstrated increased radiosensitivity compared to the AC and CC genotypes.

Interleukin 17A polymorphism elevates gene expression and is associated with increased risk of nonsmall cell lung cancer.

Interleukin 17 (IL-17), also known as IL-17A, is a proinflammatory cytokine and plays critical roles in tumor immunity. Nonsmall cell lung cancer (NSCLC) is the most common type of lung cancers. The aim of this study was to investigate the correlation between IL-17A genetic polymorphisms and susceptibility to NSCLC. Two single nucleotide polymorphisms (SNPs) in IL-17A gene, rs3819024A/G and rs8193037G/A, were detected in 322 NSCLC patients and 366 healthy donors. Data revealed that prevalence of IL-17A rs8193037GA and AA genotypes were significantly higher in the patients than in controls (odds ratio [OR]: 2.20, 95% confidence interval [CI]: 1.53-3.16, p<0.001; and OR: 3.19, 95% CI: 1.42-7.15, p=0.003). Stratification analyses showed that rs8193037A allele had significantly higher percentage in adenocarcinoma than in squamous cell carcinoma (OR: 1.72, 95% CI: 1.12-2.64, p=0.013). When examining the possible function of the SNPs, we found that in vitro stimulated peripheral blood mononuclear cells from subjects possessing rs8193037A allele produced significantly more IL-17 than those with the GG genotype, and this phenomenon could be observed in both controls and the NSCLC patients. These data indicate IL-17A polymorphism is associated with increased risk of NSCLC probably by elevating gene expression.

Genetic polymorphisms in the vitamin D pathway in relation to lung cancer risk and survival.

Studies have suggested that vitamin D may have protective effects against cancer development or tumor progression. To search for additional evidence, we investigated the role of genetic polymorphisms involved in the vitamin D pathway in non-small cell lung cancer (NSCLC). We evaluated common genetic polymorphisms associated with the vitamin D pathway in relation to NSCLC in a case-control study of 603 newly diagnosed NSCLC patients and 661 matched healthy controls. Seven single nucleotide polymorphisms (SNPs) were genotyped, the expression of CYP27B1 and CYP24A1 were measured in 153 tumor samples and their associations with genotypes and patient survival were also analyzed. In the case-control comparison, we found SNP rs3782130 (CYP27B1), rs7041 (GC), rs6068816 and rs4809957 (CYP24A1) associated with NSCLC risk. The risk of NSCLC was increased with the number of risk alleles. CYP27B1 and CYP24A1 expression were significantly different between tumor and normal tissues in NSCLC. High CYP27B1 expression was associated with better overall survival, and the expression was different by the rs3782130 genotype. The study suggests that some genetic polymorphisms involved in the vitamin D pathway may associate with NSCLC risk, and one of the polymorphisms (rs3782130) may affect gene expression and patient survival.

Interleukin 17A genetic variations and susceptibility to non-small cell lung cancer.

Lung cancer is the leading cause of cancer-related death, in which non-small cell lung cancer (NSCLC) is the most common type. Evidence have shown that interleukin 17 (IL-17) greatly involves in human immune responses. In this study, we investigated the effect of IL-17 on NSCLC by examining the association between IL-17A genetic polymorphisms and the susceptibility to NSCLC. IL-17A -420A/G and IL-17A -73G/A polymorphisms were detected in 330 NSCLC patients and 382 healthy controls. We found that subjects carrying -73GA genotype or AA genotype had 2.09-fold or 2.52-fold increased risk of NSCLC than those with -73GG genotype [odds ratio (OR)=2.09, 95% confidence interval (CI), 1.46 - 2.98, p<0.001; OR=2.52, 95% CI, 1.30-4.88, p=0.005, respectively). However, the IL-17A -420A/G did not reveal any correlation with the cancer. Further investigation showed that prevalence of IL-17A -73GA genotype and A allele were significantly increased in adenocarcinoma patients (OR=1.75, 95% CI, 1.08-2.86, p=0.024, OR=1.57, 95% CI, 1.09-2.28, p=0.016, respectively). We also evaluated the effect of the polymorphisms on gene expression, and identified that peripheral blood mononuclear cells with IL-17A -73GA and AA genotypes produced significantly higher level of IL-17 than the cells with IL-17A -73GG genotype. Our results suggest that IL-17A -73G/A genetic variations may upregulate IL-17 expression and are associated with increased susceptibility to NSCLC.

A study on the relationship between endoplasmic reticulum aminopeptidase2 genetic polymorphisms and non-small cell lung cancer in Yunnan Han population

To evaluate the association between the genetic polymorphisms of endoplasmic reticulum aminopeptidase 2 (ERAP2) and the susceptibility of non-small cell lung cancer (NSCLC) in Yunnan Han population. A total of 223 patients with NSCLC and 205 healthy controls in Yunnan Han population were included in the present study. The SNP of rs2248374 and rs2549782 in ERAP2 gene were genotyped using TaqMan fluorescence probe technique, and their haplotypes were constructed. Then, the association between the two SNPs with NSCLC was assessed. The allele A and allele G frequencies for rs2248374 in NSCLC patients and the control groups were 45.5% (203/446), 54.5% (243/446) and 37.8% (155/410), 62.2% (255/410), respectively (χ² = 5.220, P < 0.05). The genotypic GG, GT, TT for rs2549782 in NSCLC patients and the control groups were 21.5% (48/223), 48.9% (109/223), 29.6% (66/223) and 11.7% (24/205), 49.8% (102/205), 38.5% (79/205), respectively(χ² = 8.656, P < 0.05). And the allele G and allele T frequencies for rs2549782 in NSCLC patients and the control groups were 46.0% (205/446), 54.0% (241/446) and 36.6% (150/410), 63.4% (260/410), respectively (χ² = 7.741, P < 0.05). The frequencies of haplotype rs2248374/rs2549782-AG were 44.6% (199/446), 36.1% (148/410) and rs2248374/rs2549782-GT were 53.1% (237/446), 61.7% (253/410), which also showed difference between NSCLC patients and the control groups (χ² = 6.567, P < 0.01;χ² = 6.567, P < 0.01). The allele A and allele G frequencies for rs2248374 were 52.9% (72/136), 47.1% (64/136) and 42.3% (131/310), 57.7% (179/310) in the Cigarette-smoking group and the Non-smoking group, respectively (χ² = 4.498, P < 0.05), while the allele G and allele T frequencies for rs2549782 were 54.4% (74/136), 45.6% (62/136) and 42.3% (131/310), 57.7% (179/310) in the Cigarette-smoking group and the Non-smoking group, respectively(χ² = 5.831, P < 0.05). The genotypic AA,AG,GG for rs2248374 were 17.3% (24/139), 56.1% (78/139), 26.6% (37/139) and 27.8% (22/79), 38.0% (30/79), 34.2% (27/79) in lung squamous cell carcinoma and lung adenocarcinoma, respectively (χ² = 6.999, P < 0.05), while the genotypic GG, GT, TT for rs2549782 were 18.7% (26/139), 55.4% (77/139), 25.9% (36/139) and 27.8% (22/79), 36.7% (29/79), 35.4% (28/79) in lung squamous cell carcinoma and lung adenocarcinoma, respectively (χ² = 7.093, P < 0.05). ERAP2 rs2248374 and rs2549782 had a strong association with NSCLC and the pathological pattern. The rs2248374/rs2549782-AG haplotype was associated with increased NSCLC risk (OR = 1.435, 95%CI: 1.088-1.893), whereas the rs2248374/rs2549782-GT haplotype individuals may have a reduced NSCLC risk (OR = 0.697, 95%CI: 0.528-0.919).