Non-small Cell Lung Cancer Susceptibility Research Articles

Impact of IL-6 and IL-1β Gene Variants on Non-small-cell Lung Cancer Risk in Egyptian Patients

AbstractLung cancer is a serious health and life issue, with the fastest-growing incidence and fatality rates worldwide. It is now clear that inflammation is a key factor involved in all aspects of carcinogenesis, notably lung cancer development. Genetic changes, including polymorphisms in inflammatory genes, are supposed to be a significant cause of increased lung cancer risk. The main idea of this research was to disclose the linkage between both IL-6 rs1800795 and IL-1β rs16944 variants and susceptibility to non-small-cell lung cancer (NSCLC) in Egyptians. This case–control design was composed of 127 cases and 138 controls, which were genotyped using the ARMS-PCR technique. To examine the NSCLC susceptibility under various genetic models, the odds ratio (OR) and 95% confidence intervals (CIs) were determined by logistic regression. Rs1800795 of the IL-6 gene was linked to higher odds of NSCLC under the allele model (adjusted, OR 2.28; 95% CI 1.2–4.33; p = 0.011). In the genetic models, IL-6 rs1800795 elevated the odds of NSCLC, while IL-1β rs16944 decreased the odds of NSCLC. Stratification analysis showed that IL-6 rs1800795 greatly increased the NSCLC risk in females and adenocarcinoma subtypes, whereas IL-1β rs16944 largely decreased the NSCLC risk for males, patients aged < 55, and nonsmokers. Regarding clinical data, the IL-6 variant was remarkably correlated with tumor size. This work primarily established that IL-6 and IL-1β variants have a great impact on NSCLC development in the Egyptian population; thus, it may be a supportive guide for earlier NSCLC prevention.

A genetic variant in gene NDUFAF4 confers the risk of non-small cell lung cancer by perturbing hsa-miR-215 binding.

Hsa-microRNA-215 (hsa-miR-215) plays multiple roles in carcinogenesis through regulating its target genes. Genetic variants in hsa-miR-215 target sites thus may affect hsa-miR-215-mRNA interactions, result in altered expression of target genes and even influence cancer susceptibility. This study aimed to investigate the associations of genetic variants which located in the binding sites of hsa-miR-215 with non-small cell lung cancer (NSCLC) susceptibility in the Chinese population and reveal the potential regulatory mechanism of functional variants in NSCLC development. The candidate genetic variants were predicted and screened through bioinformatics analysis based on the degree of complementarity of hsa-miR-215 sequences. The potential effects of genetic variants on the binding ability of hsa-miR-215 and target genes were also predicted. A case-control study with 932 NSCLC patients and 1036 healthy controls was conducted to evaluate the association of candidate genetic variants with NSCLC susceptibility, and an independent case-control study with 552 NSCLC cases and 571 controls were used to further validate the promising associations. Dual luciferase reporter gene assay was applied to explore the regulation of the genetic variants on transcription activity of target gene. Cell phenotyping experiments in vitro and RNA sequencing (RNA-seq) were then carried out to preliminarily explore the potential regulatory mechanisms of the target genes in NSCLC. A total of five candidate genetic variants located in the binding sites of hsa-miR-215 were screened. The two-stage case-control study showed that a variant rs1854268 A > T, which located in the 3' untranslated (3'UTR) region of NDUFAF4 gene, was associated with decreased risk of NSCLC (additive model, odds ratio [OR] = 0.83, 95% confidence interval [CI]: 0.75-0.92, p < 0.001). Functional annotation displayed that rs1854268 A > T might downregulate the expression of NDUFAF4 by enhancing the binding affinity of hsa-miR-215-5p to NDUFAF4 mRNA. Additionally, transient knockdown of the NDUFAF4 could inhibit lung cancer cell migration and promote lung cancer cell apoptosis. Further RNA-seq analysis revealed that the knockdown of NDUFAF4 may affect NSCLC development by downregulating the nuclear factor kappa B (NF-κB) and phosphoinositide 3 kinase-AKT (PI3K-AKT) signaling pathways. Moreover, the overexpression of CCND1 could partially attenuate the effects of NDUFAF4 knock down on lung cancer cell migration and apoptosis, indicating that CCND1 may be involved in the tumor-promoting effects of NDUFAF4 as a downstream molecule of NDUFAF4 gene. In conclusion, the genetic variant rs1854268 (A > T) on NDUFAF4 confers NSCLC susceptibility by altering the binding affinity of hsa-miR-215-5p, thus regulating the expression of NDUFAF4 and subsequently influencing downstream tumor molecules and pathways such as CCND1, NF kappa B, and PI3K-AKT signaling pathways.

Machine Learning Study of SNPs in Noncoding Regions to Predict Non-small Cell Lung Cancer Susceptibility

Non-small cell lung cancer (NSCLC) is the most common pathological subtype of lung cancer. Both environmental and genetic factors have been reported to impact the lung cancer susceptibility. We conducted a genome-wide association study (GWAS) of 287 NSCLC patients and 467 healthy controls in a Chinese population using the Illumina Genome-Wide Asian Screening Array Chip on 712,095 SNPs (single nucleotide polymorphisms). Using logistic regression modeling, GWAS identified 17 new noncoding region SNP loci associated with the NSCLC risk, and the top three (rs80040741, rs9568547, rs6010259) were under a stringent p-value (<3.02e-6). Notably, rs80040741 and rs6010259 were annotated from the intron regions of MUC3A and MLC1, respectively. Together with another five SNPs previously reported in Chinese NSCLC patients and another four covariates (e.g., smoking status, age, low dose CT screening, sex), a predictive model by machine learning methods can separate the NSCLC from healthy controls with an accuracy of 86%. This is the first time to apply machine learning method in predicting the NSCLC susceptibility using both genetic and clinical characteristics. Our findings will provide a promising method in NSCLC early diagnosis and improve our understanding of applying machine learning methods in precision medicine.

Association between Polymorphism of Genes IL-1A, NFKB1, PAR1, TP53, and UCP2 and Susceptibility to Non-Small Cell Lung Cancer in the Brazilian Amazon.

Non-small cell lung cancer (NSCLC) accounts for the vast majority of cases of lung neoplasms. It is formed in multiple stages, with interactions between environmental risk factors and individual genetic susceptibility and with genes involved in the immune and inflammatory response paths, cell or genome stability, and metabolism, among others. Our objective was to evaluate the association between five genetic variants (IL-1A, NFKB1, PAR1, TP53, and UCP2) and the development of NSCLC in the Brazilian Amazon. The study included 263 individuals with and without lung cancer. The samples were analyzed for the genetic variants of NFKB1 (rs28362491), PAR1 (rs11267092), TP53 (rs17878362), IL-1A (rs3783553), and UCP2 (INDEL 45-bp), which were genotyped in PCR, followed by an analysis of the fragments, in which we applied a previously developed set of informative ancestral markers. We used a logistic regression model to identify differences in the allele and the genotypic frequencies among individuals and their association with NSCLC. The variables of gender, age, and smoking were controlled in the multivariate analysis to prevent confusion by association. The individuals that were homozygous for the Del/Del of polymorphism NFKB1 (rs28362491) (p = 0.018; OR = 0.332) demonstrate a significant association with NSCLC, which was similar to that observed in the variants of PAR1 (rs11267092) (p = 0.023; OR = 0.471) and TP53 (rs17878362) (p = 0.041; OR = 0.510). Moreover, the individuals with the Ins/Ins genotype of polymorphism IL-1A (rs3783553) demonstrated greater risk for NSCLC (p = 0.033; OR = 2.002), as did the volunteers with the Del/Del of UCP2 (INDEL 45-bp) (p = 0.031; OR = 2.031). The five polymorphisms investigated can contribute towards NSCLC susceptibility in the population of the Brazilian Amazon.

The Interaction between Four Polymorphisms and Haplotype of ABCB1, the Risk of Non-Small Cell Lung Cancer, and the Disease Phenotype.

P-glycoprotein, product of the ABCB1 (ATP binding cassette subfamily B member 1) gene, has been reported to play an important role in multiple drug resistance during cancer therapy. However, its influence on non-small cell lung cancer (NSCLC) risk has not been clearly defined. The aim of the present study was to examine the association between clinicopathological factors and SNPs T-129C, C1236T, G2677T/A, and C3435T, as well as its haplotype, and to investigate the role of ABCB1 polymorphisms in NSCLC development. The study included 80 patients who suffered from NSCLC and underwent surgery to remove the tumour and 96 healthy controls. The tissues were genotyped by PCR-RFLP and sequencing methods, and the haplotype frequencies in both groups were estimated. The SNP C3435T was identified as a NSCLC risk factor. The presence of mutated allelic variant T (p=0.0103) or homozygote TT (p=0.0099) was observed significantly more often in cancer patients than in healthy controls. The two groups also demonstrated a highly significant difference in common haplotype frequency (p=0.01). The T-129-T1236-T2677-T3435 haplotype was found to be most closely associated with NSCLC risk. Although the investigated polymorphisms were not related to demographic features, clinicopathological lung tumour characteristics, or blood morphology indices, marginally significant correlations were found with some variables: C1236T with age of disease onset (p=0.0410); C3435T with smoking status (p=0.0561). As the findings indicate, lung cancer and control groups demonstrate significantly different patterns of -129/1236/2677/3435 haplotype distribution; T-T-T-T haplotype contributes to NSCLC susceptibility, and this effect is probably mainly dependent on C3435T. So far, similar studies were published in other populations.

Exogenous proline enhances susceptibility of NSCLC to cisplatin via metabolic reprogramming and PLK1-mediated cell cycle arrest.

The occurrence of cisplatin resistance is still the main factor limiting the therapeutic effect of non-small cell lung cancer (NSCLC). It is urgent to elucidate the resistance mechanism and develop novel treatment strategies. Targeted metabolomics was first performed to detect amino acids’ content in cisplatin-resistant cancer cells considering the relationship between tumour metabolic rearrangement and chemotherapy resistance and chemotherapy resistance. We discovered that levels of most amino acids were significantly downregulated, whereas exogenous supplementation of proline could enhance the sensitivity of NSCLC cells to cisplatin, evidenced by inhibited cell viability and tumour growth in vitro and xenograft models. In addition, the combined treatment of proline and cisplatin suppressed ATP production through disruption of the TCA cycle and oxidative phosphorylation. Furthermore, transcriptomic analysis identified the cell cycle as the top enriched pathway in co-therapy cells, accompanied by significant down-regulation of PLK1, a serine/threonine-protein kinase. Mechanistic studies revealed that PLK1 inhibitor (BI2536) and CDDP have synergistic inhibitory effects on NSCLC cells, and cells transfected with lentivirus expressing shPLK1 showed significantly increased toxicity to cisplatin. Inhibition of PLK1 inactivated AMPK, a primary regulator of cellular energy homeostasis, ultimately leading to cell cycle arrest via FOXO3A-FOXM1 axis mediated transcriptional inhibition in cisplatin-resistant cells. In conclusion, our study demonstrates that exogenous proline exerts an adjuvant therapeutic effect on cisplatin resistance, and PLK1 may be considered an attractive target for the clinical treatment of cisplatin resistance in NSCLC.

Association between TP53, PAR1 and CCR5 gene polymorphisms and non-small cell lung cancer susceptibility in the Amazon.

e20538 Background: Lung cancer is one of the most frequent neoplasms in the world, representing 11.4% of all registered cancers, and is responsible for 18% of cancer deaths. It is divided into two categories, small cell lung cancer, responsible for 15% of cases; and non-small cell lung cancer (NSCLC), which represents 85% of cases. The most well-known risk factor for the development of lung cancer is smoking, due to substances contained in tobacco associated with inflammation and carcinogenesis. Pulmonary carcinogenesis is a complex and gradual process, with synergistic and complex interactions between environmental risk factors and individual genetic susceptibility. The aim of this study was to investigate possible associations between TP53, PAR1, and CCR5 gene polymorphism for susceptibility to NSCLC in the Amazon. Methods: This is a pilot, case-control study, which included 263 subjects, 67 patients with NSCLC and 196 healthy subjects. The samples were analyzed for TP53 (rs17880560), PAR1 (rs11267092), and CCR5 (rs333) gene polymorphism, genotyped in PCR, followed by fragment analysis. To avoid misinterpretation due to population substructure, we applied a previously developed set of 61 informative ancestral markers that were genotyped by multiplex PCR. We used logistic regression to identify differences in genotypic frequencies between individuals with and without lung cancer. Results: We observed that some genotypes were associated with protection for NSCLC: TP53 gene LED/DEL genotype (p = 0.041, OR: 0.510, 95%CI: 0.267-0.974); DEL/DEL genotype of the PAR1 gene (p = 0.023, OR: 0.471, 95%CI: 0.247-0.971); and also the INS/INS genotype of the CCR5 gene (p = 0.033, OR: 0.331, 95%CI: 0.120-0.917). Conclusions: TP53 (rs17880560), PAR1 (rs11267092) and CCR5 (rs333) gene variants were significantly associated with NSCLC in patients from the Amazon. The validation of these findings may favor, in the future, the screening of individuals, facilitating the institution of preventive measures personalized, early diagnosis, consequently reducing the cost for health services and mortality from this malignant neoplasm. Keywords: Genetic Polymorphism; TP53; PAR1; CCR5; Biomarker; Non-Small Cell Lung Cancer.

The Polymorphism and Expression of EGFL7 and miR-126 Are Associated With NSCLC Susceptibility.

Previous investigations have reported that microRNA-126 (miR-126) and its host gene, epidermal growth factor-like domain-containing protein 7 (EGFL7) are involved in lung cancer progression, suggesting EGFL7 and miR-126 play a joint role in lung cancer development. In this study, we analyzed the methylation-associated regulation of EGFL7 and miR-126 in non-small cell lung cancer (NSCLC) and further investigated the association between EGFL7/miR-126 polymorphisms and NSCLC susceptibility in the Han Chinese population. Based on our data, relative to those in adjacent normal tissue, both EGFL7 expression and miR-126 expression were decreased significantly in lung cancer tissue (P = 3x10-4 and P < 1x10-4), and the expression of EGFL7 mRNA and miR-126 was significantly correlated in both NSCLC tissue n = 46, r = 0.43, P = 0.003 and adjacent normal tissue n = 46, r = 0.37, P = 0.011. Differential methylation analysis indicated that methylation levels of multiple CG loci in EGFL7 were significantly higher in the lung cancer samples than in the normal samples (P < 0.01). Moreover, EGFL7 mRNA and miR-126 were significantly upregulated after treatment with the DNA demethylating agent 5-aza-2′-deoxycytidine (5-Aza-CdR) in lung cancer cell lines. In addition, the A allele of rs2297538 was significantly associated with a decreased NSCLC risk (OR = 0.68, 95% CI: 0.52~0.88), and the expression of EGFL7 and miR-126 was significantly lower in rs2297538 homozygous G/G tumor tissue than in A/G+A/A tumor tissue (P = 0.01 and P = 0.002). Our findings suggest that the expression of EGFL7 and miR-126 in NSCLC can be concomitantly downregulated through methylation and the EGFL7/miR-126 polymorphism rs2297538 is correlated with NSCLC risk. Together, these results provide new insights into the pathogenesis of NSCLC.

A Functional Polymorphism in Accessible Chromatin Region Confers Risk of Non-Small Cell Lung Cancer in Chinese Population.

BackgroundThe disease-associated non-coding variants identified by genome-wide association studies (GWASs) were enriched in open chromatin regions (OCRs) and implicated in gene regulation. Genetic variants in OCRs thus may exert regulatory functions and contribute to non-small cell lung cancer (NSCLC) susceptibility.ObjectiveTo fine map potential functional variants in GWAS loci that contribute to NSCLC predisposition using chromatin accessibility and histone modification data and explore their functions by population study and biochemical experimental analyses.MethodsWe mapped the chromatin accessible regions of lung tissues using data of assay for transposase-accessible chromatin using sequencing (ATAC-seq) in The Cancer Genome Atlas (TCGA) and prioritized potential regulatory variants within lung cancer GWAS loci by aligning with histone signatures using data of chromatin immunoprecipitation assays followed by sequencing (ChIP-seq) in the Encyclopedia of DNA Elements (ENCODE). A two-stage case–control study with 1,830 cases and 2,001 controls was conducted to explore the associations between candidate variants and NSCLC risk in Chinese population. Bioinformatic annotations and biochemical experiments were performed to further reveal the potential functions of significant variants.ResultsSixteen potential functional single-nucleotide polymorphisms (SNPs) were selected as candidates from bioinformatics analyses. Three variants out of the 16 candidate SNPs survived after genotyping in stage 1 case–control study, and only the results of SNP rs13064999 were successfully validated in the analyses of stage 2 case–control study. In combined analyses, rs13064999 was significantly associated with NSCLC risk [additive model; odds ratio (OR) = 1.17; 95%CI, 1.07–1.29; p = 0.001]. Functional annotations indicated its potential enhancer bioactivity, and dual-luciferase reporter assays revealed a significant increase in luciferase activity for the reconstructed plasmid with rs13064999 A allele, when compared to the one with wild-type G allele (pA549 < 0.001, pSK-MES-1 = 0.004). Further electrophoretic mobility shift assays (EMSA) and super-shift assays confirmed a stronger affinity of HP1γ for the binding motif containing SNP rs13064999 A allele.ConclusionThese findings suggested that the functional variant rs13064999, identified by the integration of ATAC-seq and ChIP-seq data, contributes to the susceptibility of NSCLC by affecting HP1γ binding, while the exact biological mechanism awaits further exploration.

Role of ERCC5 polymorphisms in non‑small cell lung cancer risk and responsiveness/toxicity to cisplatin‑based chemotherapy in the Chinese population.

Non‑small cell lung cancer (NSCLC) is the leading cause of cancer‑related deaths worldwide. Cisplatin‑based chemotherapy currently represents the main treatment option for patients with NSCLC. The aim of the present study was to evaluate effect of single nucleotide polymorphisms(SNPs) within the excision repair cross‑complementing group5(ERCC5) gene on susceptibility to NSCLC, as well as the responsiveness to and toxicity of cisplatin chemotherapy. A total of 506patients with NSCLC and 510 healthy controls were recruited for the present study. All DNA samples were genotyped by the Agena MassARRAY platform. Logistic regression analysis was carried out to assess the relationship between ERCC5 polymorphisms with NSCLC susceptibility and responsiveness to chemotherapy. The rs4771436 TG‑GG genotype was associated with increased NSCLC risk. When the data were stratified according to age, sex, tobacco smoking, body mass index and histological type, ERCC5 polymorphisms (rs2016073, rs4771436, rs11069498 and rs4150330) were associated with NSCLC risk. Furthermore, the A allele and GA‑AA genotype of rs11069498 were related to the response to chemotherapy. ERCC5 (rs11069498 and rs4150330) polymorphisms were associated with the increased risk of toxicity. However, rs4771436 in ERCC5 gene was significantly correlated with the reduced risk of toxicity. These results suggested a potential relationship between ERCC5 polymorphisms, the risk of NSCLC and the sensitivity to cisplatin‑based chemotherapy among Chinese populations.

Contribution of XPD and XPF Polymorphisms to Susceptibility of Non-Small Cell Lung Cancer in High-Altitude Areas

Background: We aimed to explore the relation of XPD and XPF variants with non-small cell lung cancer (NSCLC) risk and the effect of these variants on the sensitivity to cisplatin-based chemotherapy among the Chinese Han population in high-altitude areas. Methods: Eight single-nucleotide polymorphisms (SNPs) in XPD and XPF were genotyped by Agena MassARRAY platform among 506 NSCLC cases and 510 healthy controls. Correlation of XPD and XPF gene polymorphisms with NSCLC susceptibility and the response of cis­platin-based chemotherapy were analyzed with logistic regression by calculating odds ratios (ORs) and 95% confidence intervals (CIs). Results: XPD rs13181 (OR = 1.53, 95% CI: 1.04–2.24, p = 0.029) and rs1052555 (OR = 1.63, 95% CI: 1.05–2.53, p = 0.029) possibly contributed to the increased risk of lung adenocarcinoma, while XPD rs238406 (OR = 0.63, 95% CI: 0.43–0.94, p = 0.024) was a protective factor for lung squamous cell carcinoma. Age, gender, BMI, smoking, and drinking might affect the correlation of XPD and XPF polymorphisms with NSCLC risk. More importantly, XPD rs13181 (OR = 2.91, p = 0.015), XPD rs1052555 (OR = 2.67, p = 0.022), and XPF rs231127 (OR = 4.15, p = 0.008) were associated with treatment response in NSCLC patients underwent cisplatin-based chemotherapy. Conclusion: This study found that XPD and XPF variants might contribute to NSCLC risk and the response of cisplatin-based chemotherapy among the Chinese Han population in high-altitude areas.

CYP3A4 genetic variants are associated with susceptibility of non-small cell lung cancer in a Shaanxi Han population

PurposeLung cancer (LC) is one of the fastest-growing malignant tumors in the world in terms of morbidity and mortality. CYP3A4 plays a crucial role in the occurrence of LC. Little is known about the contribution of CYP3A4 polymorphisms for non-small cell lung cancer (NSCLC) risk. This study aimed to explore the correlation of CYP3A4 genetic variants (rs3735451, rs4646440, rs35564277, and rs4646437) with NSCLC risk. MethodsFour single nucleotide polymorphisms (SNPs) were genotyped by Agena MassARRAY in this case-control study (507 NSCLC patients and 505 controls) among a Shaanxi Han population. Hardy-Weinberg equilibrium (HWE) of each SNP in controls was evaluated by exact test. The association of CYP3A4 polymorphisms with NSCLC risk was explored by calculating odds ratios (OR) and 95% confidence intervals (CI) using logistic regression analysis with adjustment for age and gender. ResultsOur research revealed that rs4646440 was significantly associated with an increased risk of NSCLC (OR 2.64, p = .005), while rs4646437 played a protective role in NSCLC risk (OR 0.48, p = 4.00 × 10−7). Stratified analyses indicated that rs4646440 significantly enhanced the susceptibility of NSCLC in BMI > 24 kg/m2, non-smokers and non-drinkers (OR 14.29, p = .012; OR 1.56, p = .023; OR 1.67, p = .031, respectively). Besides, we observed that rs3735451 exhibited an increased risk of NSCLC in BMI > 24 kg/m2 (OR 2.47, p = .030), whereas rs4646437 had a reduced risk of NSCLC in BMI ≤ 24 kg/m2 (OR 0.47, p = 5.17 × 10−5). We also found that rs35564277 was considered as a protective factor of NSCLC in non-smokers (OR 0.50, p = .032). ConclusionOur study indicated that CYP3A4 genetic variants were associated with NSCLC susceptibility in a Shaanxi Han population.

The risk variant rs884225 within EGFR impairs miR-103a-3p's anti-tumourigenic function in non-small cell lung cancer.

Epidermal growth factor receptor (EGFR) status is the major determinant of non-small cell lung cancer (NSCLC) therapy selection. Studies have hinted that EGFR antibodies or tyrosine kinase inhibitors were beneficial in patients with EGFR mutation-negative but EGFR-overexpressing of NSCLC. However, the mechanisms underlying EGFR amplification and overexpression in NSCLC remain largely unknown. Here, we report that rs884225, a single nucleotide polymorphism in the EGFR 3'-terminal untranslated region, was significantly associated with EGFR expression level and contributed to NSCLC susceptibility. Mechanistically, the rs884225 C allele enhanced EGFR expression by altering the miR-103a-3p binding site, thus impairing miR-103a-3p's anti-tumourigenic function. As a tumour suppressor gene, miR-103a-3p expression correlated with overall and recurrence-free survival in NSCLC patients. Furthermore, miR-103a-3p inhibited growth and metastasis via effects on the KRAS pathway and epithelial-to-mesenchymal transition in EGFR wild-type NSCLC cell lines, respectively, which substantially reduced EGFR expression and activity. Thus, rs884225 may be a biomarker for NSCLC susceptibility, and miR-103a-3p may be a potential therapeutic target in NSCLC.

Genome-wide haplotype association study identifies risk genes for non-small cell lung cancer

Lung cancer is the leading cause of cancer-related death worldwide. Most lung cancer is non-small cell lung cancer (NSCLC), in which malignant cells form in the lung epithelium. Mutations in multiple genes and environmental factors both contribute to NSCLC, and although some NSCLC susceptibility genes have been characterized, the pathogenesis of this disease remains unclear. To identify genes conferring NSCLC risk and determine their associated pathological mechanism, we combined genome-wide haplotype associated analysis with gene prioritization using 224,677 SNPs in 37 NSCLC cell lines and 116 unrelated European individuals. Five candidate genes were identified: ESR1, TGFBR1, INSR, CDH3, and MAP3K5. All of these have previously been implicated in NSCLC, with the exception of CDH3, which can therefore be considered a novel indicator of NSCLC risk. Functional annotation confirmed the relationship between these five genes and NSCLC. Our findings are indicative of the underlying pathological mechanisms of NSCLC and provide information to support future directions in diagnosing and treating NSCLC.

Relationship between IGF2BP2 and IGFBP3 polymorphisms and susceptibility to non-small-cell lung cancer: a case-control study in Eastern Chinese Han population.

BackgroundIGF2BP2 and IGFBP3 polymorphisms may be associated with cancer risk.MethodsWith an aim to determine the association of variations in IGF2BP2 and IGFBP3 genes with risk of non-small-cell lung cancer (NSCLC), IGF2BP2 rs1470579 A>C, rs4402960 G>T and IGFBP3 rs2270628 C>T, rs3110697 G>A, and rs6953668 G>A polymorphisms were selected and genotyped in 521 NSCLC patients and 1,030 controls.ResultsWe found that there was no difference in IGF2BP2 and IGFBP3 genotype distribution among the NSCLC patients and controls. The stratified analyses suggested that IGF2BP2 rs1470579 A>C polymorphism decreased the risk of NSCLC in some subgroups (female subgroup: CC vs AA: adjusted P=0.032 and CC vs AC/AA: adjusted P=0.028; <60 years subgroup: CC vs AA: adjusted P=0.012 and CC vs AC/AA: adjusted P=0.013; and never drinking subgroup: CC vs AA: adjusted P=0.046 and CC vs AC/AA: adjusted P=0.031). The stratified analyses also found that IGF2BP2 rs4402960 G>T polymorphism decreased the risk of NSCLC in some subgroups (female subgroup: TT vs GG: adjusted P=0.031 and TT vs GT/GG: adjusted P=0.026; <60 subgroup: TT vs GG: adjusted P=0.037 and TT vs GT/GG: adjusted P=0.038; and never drinking subgroup: TT vs GT/GG: adjusted P=0.046). Haplotype analysis indicated Ars1470579Crs2270628Grs3110697Grs4402960Ars6953668 haplotype decreased susceptibility of NSCLC (P=0.007).ConclusionOur study suggests that IGF2BP2 rs1470579 A>C, rs4402960 G>T single-nucleotide polymorphisms are candidates for decreased susceptibility to NSCLC among female, <60 years, and never drinking subgroups. In the future, more case–control studies with functional analysis are needed to confirm these preliminary findings.

Methylenetetrahydrofolate reductase tagging polymorphisms are associated with risk of non-small cell lung cancer in eastern Chinese Han population.

Previous reports implicated 5,10-ethylenetetrahydrofolate reductase (MTHFR) polymorphisms acted as a potential risk factor for several cancers. In order to explore the effect of MTHFR SNPs on non-small cell lung cancer (NSCLC), we selected MTHFR tagging single nucleotide polymorphisms (SNPs) and carried out a case-control study to determine the potential relationship of MTHFR SNPs with NSCLC risk. Our study consisted of 521 NSCLC patients and 1,030 non-cancer controls. MTHFR SNPs were genotyped by SNPscanTM genotyping assay. Using four genetic models (additive, Homozygote, dominant, recessive), the genotype frequencies were compared using the chi-squared (χ2) test. Crude/adjusted odds ratios (ORs) with their 95% confidence intervals (CIs) were used to assess the difference for the genotype distribution. We found that MTHFR rs1801133 G>A polymorphism decreased the risk of overall NSCLC. In a subgroup analysis, MTHFR rs1801133 G>A polymorphism also decreased NSCLC risk in female, < 60 years and never smoking subgroups. However, we identified that MTHFR rs4845882 G>A polymorphism was associated with the development of NSCLC in female subgroup. In addition, MTHFR rs9651118 T>C polymorphism increased the risk of NSCLC in < 60 years, never smoking and BMI < 24 kg/m2 subgroups. In conclusion, the current study highlights MTHFR rs1801133 G>A variants decreases the risk of NSCLC. Nevertheless, MTHFR rs4845882 G>A and rs9651118 T > C polymorphisms may be associated with NSCLC susceptibility. Well-designed large-scale studies are needed to confirm these findings and explore the interactions of gene-gene and gene-environment involved in MTHFR SNPs and NSCLC.

Impact of DNA repair, folate and glutathione gene polymorphisms on risk of non small cell lung cancer

Lung cancer, particularly non-small cell lung cancer (NSCLC) subtype, is the leading cause of cancer-related death related worldwide. Numerous gene polymorphisms in DNA repair, folate and glutathione pathways have been associated with susceptibility of NSCLC. We conducted this study to evaluate the effects of ERCC1, ERCC2, ERCC5, XRCC1, XRCC3, MTHFR, MTR, MTHFD1, SLC19A1 and GSTP1 gene polymorphisms on risk of NSCLC.No association between these gene polymorphisms and susceptibility of NSCLC were found in our patients, suggesting that genetic variations in genes involved in DNA repair, folate and glutathione metabolism pathways may not influence the risk of NSCLC.

Genetic variant of miR-4293 rs12220909 is associated with susceptibility to non-small cell lung cancer in a Chinese Han population.

Non-small cell lung cancer is one of the most common cancers and the leading cause of cancer death worldwide. Genetic variants in regulatory regions of some miRNAs might be involved in non-small cell lung cancer susceptibility and survival. rs12220909 (G/C) genetic polymorphism in miR-4293 has been shown to be associated with decreased risk of esophageal squamous cell carcinoma. However, the influence of rs12220909 genetic variation on non-small cell lung cancer susceptibility has not been reported. In order to evaluate the potential association between miR-4293 rs12220909 and non-small cell lung cancer risk in a Chinese population, we performed a case-control study among 998 non-small cell lung cancer cases and 1471 controls. The data shows that miR-4293 rs12220909 was significantly associated with decreased susceptibility to non-small cell lung cancer (GC vs.GG: OR = 0.681, 95%CI = 0.555–0.835, P = 2.19E-4; GG vs. GC+CC: OR = 0.687, 95%CI = 0.564–0.837, P = 1.95E-4), which indicates that rs12220909 in miR-4293 may play a significant role in the development of non-small cell lung cancer.

O2⋅− and H2O2-Mediated Disruption of Fe Metabolism Causes the Differential Susceptibility of NSCLC and GBM Cancer Cells to Pharmacological Ascorbate

Pharmacological ascorbate has been proposed as a potential anti-cancer agent when combined with radiation and chemotherapy. The anti-cancer effects of ascorbate are hypothesized to involve the autoxidation of ascorbate leading to increased steady-state levels of H2O2; however, the mechanism(s) for cancer cell-selective toxicity remain unknown. The current study shows that alterations in cancer cell mitochondrial oxidative metabolism resulting in increased levels of O2⋅- and H2O2 are capable of disrupting intracellular iron metabolism, thereby selectively sensitizing non-small-cell lung cancer (NSCLC) and glioblastoma (GBM) cells to ascorbate through pro-oxidant chemistry involving redox-active labile iron and H2O2. In addition, preclinical studies and clinical trials demonstrate the feasibility, selective toxicity, tolerability, and potential efficacy of pharmacological ascorbate in GBM and NSCLC therapy.

The rs1550117 A&gt;G variant in DNMT3A gene promoter significantly increases non-small cell lung cancer susceptibility in a Han Chinese population

In this study, we conducted a case-control study to explore the association between rs1550117 A>G variant of DNMT3A gene promoter and non-small cell lung cancer (NSCLC) susceptibility in a Han Chinese population. The genotyping of rs1550117 A>G variant was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and confirmed by sequencing. Allele G of rs1550117 was associated with an increased risk of NSCLC. Moreover, individuals carrying the GG genotypes had a higher risk to develop NSCLC than the AA and GA genotype carriers. Further stratified analysis showed that rs1550117 A>G was significantly related to age (> 60 years), male, smoking and drinking. In vivo detection of DNMT3A mRNA levels in NSCLC tissues and in vitro luciferase assays consistently showed that the allele G significantly decreased DNMT3A transcription. Additional functional analysis revealed that the increased binding affinity of transcription repressor SP1, which was associated with allele G of rs1550117, led to the significant decreased expression of DNMT3A. Collectively, our results propose a suppression role of DNMT3A in NSCLC development and emphasize the dual roles of DNMT3A in tumorigenesis.