Non-smoking Female Lung Cancer Research Articles

Association of polycyclic aromatic hydrocarbons exposure scores and alteration of mitochondrial DNA copy number with female lung cancer risk among never smokers

To investigate the association of exposure to polycyclic aromatic hydrocarbons exposure scores and alteration of relative mitochondrial DNA copy number of blood with female lung cancer risk among never smokers. From August 2017 to August 2021, we enrolled all physician diagnosed new cases(n=465) of non-smoking female lung cancer from 12 tertiary and above hospitals in Liaoning, Jiangsu, Anhui and Qinghai provinces. And we selected matched non-smoking controls(n=463) by age and sex who were non-cancer and noncommunicable disease patients from the same hospital visited by the cases. Blood mitochondrial DNA copy number was detected by quantitative real-time polymerase chain reaction and estimated by relative quantification. We performed random forest and logistic regression to analyze the association of polycyclic aromatic hydrocarbons exposure scores and relative mitochondrial DNA copy number with the risk of female lung cancer among never smokers. We further analyzed the mediating effect and interaction models of polycyclic aromatic hydrocarbons exposure scores and mitochondrial DNA copy number levels on lung cancer in non-smoking women. The M(P25, P75) of polycyclic aromatic hydrocarbons exposure scores for cases and controls were 0.05(0.13, 0.16) and 0.08(0.24, 0.13), polycyclic aromatic hydrocarbons exposure scores of the cases was significantly higher than the controls(U=92130, P<0.05). The M(P25, P75) of mitochondrial DNA copy number for cases and controls were 0.90(0.71, 1.14) and 1.00(0.79, 1.21), mitochondrial DNA copy number of the cases was significantly lower than the controls(U=122559, P<0.05). Random forest and multivariable logistic regression analysis showed that the risk of lung cancer in non-smoking women increased with the increase of polycyclic aromatic hydrocarbons exposure scores(P_(trend)<0.05) and the decrease of relative mitochondrial DNA copy number(P_(trend)<0.05). The additive interaction between polycyclic aromatic hydrocarbons exposure scores and mitochondrial DNA copy number in non-smoking female lung cancer was statistically significant [API = 0.43(95%CI 0.19-0.67), SI = 2.84(95%CI 1.25-6.48). Mediation analysis showed mitochondrial DNA copy number had no significant mediating effect on the association between polycyclic aromatic hydrocarbons exposure scores and lung cancer in non-smoking women(Za×Zb: 95%CI-0.044-0.055). Minimize unnecessary polycyclic aromatic hydrocarbons exposures might significantly reduce the lung cancer risk among non-smoking women. Alteration of mitochondrial DNA copy number might become a potential biomarker in risk prediction of lung cancer of non-smoking women.

Polymorphisms in Neuronal Growth Regulator 1 and Otoancorin Alternate the Susceptibility to Lung Cancer in Chinese Nonsmoking Females.

Cell adhesion molecules (CAMs) play crucial roles in the genesis and progress of tumor. We investigated the effects of single nucleotide polymorphisms (SNPs) of CAMs, neuronal growth regulator 1 (NEGR1), and Otoancorin (OTOA) on lung cancer susceptibility in Chinese nonsmoking females. Logistic regression and Cox regression analyses were conducted to investigate the effects of SNPs and environmental factors. For rs3102911, genotype TT carriers decreased the risk of lung cancer with an odds ratio (OR) of 0.635. AA genotypes of rs741718 increased the risk of lung cancer with an OR of 3.527. In stratified analysis, genotype AA carriers of rs741718 had a high susceptibility to lung adenocarcinoma compared with GG and AG genotypes. Analyses of association between SNPs and clinical characteristics revealed that rs3102911 as a protective factor and rs741718 as a risk factor influenced the lung cancer occurrence and progression in nonsmoking females.

A Case/Control Study: AGBL1 Polymorphism Related to Lung Cancer Risk in Chinese Nonsmoking Females.

ATP/GTP binding protein like 1 (AGBL1) plays a role in controlling the length of polyglutamate side chains. Polymorphism rs4513061 in AGBL1 is suspected to influence the risk of lung cancer. A case/control study was performed involving 556 cases and 563 controls from a hospital participating in donation. The relationship between rs4513061 and the risk of lung cancer and the interaction between rs4513061 and environmental exposure were determined by the chi-square tests, logistic regression analysis, and crossover analysis. The survival analysis was conducted by Cox proportional hazard regression. The results showed that rs4513061 polymorphism is associated with the risk of lung cancer. The stratified analysis suggested the protective effect of rs4513061 to different histological types of lung cancer, including lung adenocarcinoma (AA vs. GG: odds ratio [OR] = 0.505, 95% confidence interval [CI] = 0.337-0.756, p < 0.001), squamous cell lung cancer (AG vs. GG: OR = 0.488, 95% CI = 0.269-0.883, p = 0.018), and small-cell lung cancer (AA vs. GG: OR = 0.421, 95% CI = 0.216-0.819, p = 0.011). Nevertheless, there was no significant interaction between rs4513061 and cooking oil fume. Significant impact was not observed between the rs4513061 polymorphism and survival time of lung cancer. Our study indicated that rs4513061 in AGBL1 decreases the risk of lung cancer in nonsmoking females from northeast China.

Association Between Two Polymorphisms in the Promoter Region of miR-143/miR-145 and the Susceptibility of Lung Cancer in Northeast Chinese Nonsmoking Females.

Lung cancer is known to cause high mortality and morbidity. The study aimed to explore the association between rs3733845 and rs3733846 polymorphisms in the promoter region of miR-143/145 and the risk of lung cancer among 575 nonsmoking cases and 575 cancer-free controls in a Chinese female population. We genotyped two single nucleotide polymorphisms (SNPs) in the promoter region of miR-143/145 in 575 cases and 575 controls using TaqMan allelic discrimination method. Logistic regression analysis was conducted to assess the association between polymorphisms in the promoter of miR-143/miR-145 and risk of lung cancer females. Crossover analysis was used to explore the interaction between the two SNPs and environmental risk factors (cooking oil fume exposure and passive smoking exposure). The results showed that both rs3733845 and rs3733846 polymorphisms were associated with an increased lung adenocarcinoma risk in dominant model (adjusted odds ratio [OR] = 1.329, 95% confidence intervals [CIs] = 1.026-1.723, p = 0.031 and adjusted OR = 1.450, 95% CI = 1.112-1.890, p = 0.006, respectively). The results of crossover analysis revealed that rs3733845 and rs3733846 risk genotypes along with cooking oil exposure increased lung cancer risk by 1.862-fold and 2.260-fold, respectively (adjusted OR = 1.862, 95% CI = 1.105-3.138, p = 0.020 for rs3733845; adjusted OR = 2.260, 95% CI = 1.354-3.769, p = 0.002 for rs3733846). There was positive multiplicative interaction between the two SNPs and cooking oil fume exposure (adjusted OR = 1.362, 95% CI = 1.078-1.719, p = 0.009 for oil × rs3733845; adjusted OR = 1.399, 95% CI = 1.122-1.745, p = 0.003 for oil × rs3733846). In nonsmoking females, rs3733845 and rs3733846 polymorphisms might be associated with lung adenocarcinoma risk. Moreover, the interactions between the two SNPs and cooking oil fume exposure were statistically significant on a multiplicative scale rather than an addictive scale.

Identification of Key Genes and Pathways in Female Lung Cancer Patients Who Never Smoked by a Bioinformatics Analysis.

Smoking is considered the major risk factor for lung cancer, but only a small portion of female lung adenocarcinoma patients are associated with smoking. Thus, identifying crucial genes and pathways related to nonsmoking female lung cancer patients is of great importance. Gene expression profiles were downloaded from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) databases. The R software packages were applied to screen the differentially expressed genes (DEGs). GO term enrichment and KEGG pathway analyses were carried out using DAVID tools. The protein-protein interaction (PPI) network was constructed by Cytoscape software. In total, 487 downregulated and 199 upregulated DEGs were identified. The down-regulated DEGs were mainly enriched for behavior and response to wounding, and the upregulated DEGs were significantly enriched for multicellular organismal metabolic process and cell division. The KEGG pathway analysis revealed that the downregulated DEGs were significantly enriched for cell adhesion molecules and neuroactive ligand-receptor interaction, while the upregulated DEGs were mainly enriched for cell cycle and the p53 signaling pathway. The top 10 hub genes and top 3 gene interaction modules were selected from the PPI network. Of the ten hub genes, a high expression of five genes was related to a poor OS in female lung cancer patients who never smoked, including IL6, CXCR2, FPR2, PPBP and HBA1. However, a low expression of GNG11, LRRK2, CDH5, CAV1 and SELE was associated with a worse OS for the female lung cancer patients who never smoked. In conclusion, our study provides novel insight for a better understanding of the pathogenesis of nonsmoking female lung cancer, and these identified DEGs may serve as biomarkers for diagnostics and treatment.

Dysbiosis of the Salivary Microbiome Is Associated With Non-smoking Female Lung Cancer and Correlated With Immunocytochemistry Markers.

Background: Association between oral bacteria and increased risk of lung cancer have been reported in several previous studies, however, the potential association between salivary microbiome and lung cancer in non-smoking women have not been evaluated. There is also no report on the relationship between immunocytochemistry markers and salivary microbiota.Method: In this study, we assessed the salivary microbiome of 75 non-smoking female lung cancer patients and 172 matched healthy individuals using 16S rRNA gene amplicon sequencing. We also calculated the Spearman's rank correlation coefficient between salivary microbiota and three immunohistochemical markers (TTF-1, Napsin A and CK7).Result: We analyzed the salivary microbiota of 247 subjects and found that non-smoking female lung cancer patients exhibited oral microbial dysbiosis. There was significantly lower microbial diversity and richness in lung cancer patients when compared to the control group (Shannon index, P < 0.01; Ace index, P < 0.0001). Based on the analysis of similarities, the composition of the microbiota in lung cancer patients also differed from that of the control group (r = 0.454, P < 0.001, unweighted UniFrac; r = 0.113, P < 0.01, weighted UniFrac). The bacterial genera Sphingomonas (P < 0.05) and Blastomonas (P < 0.0001) were relatively higher in non-smoking female lung cancer patients, whereas Acinetobacter (P < 0.001) and Streptococcus (P < 0.01) were higher in controls. Based on Spearman's correlation analysis, a significantly positive correlation can be observed between CK7 and Enterobacteriaceae (r = 0.223, P < 0.05). At the same time, Napsin A was positively associated with genera Blastomonas (r = 0.251, P < 0.05). TTF-1 exhibited a significantly positive correlation with Enterobacteriaceae (r = 0.262, P < 0.05). Functional analysis from inferred metagenomes indicated that oral microbiome in non-smoking female lung cancer patients were related to cancer pathways, p53 signaling pathway, apoptosis and tuberculosis.Conclusions: The study identified distinct salivary microbiome profiles in non-smoking female lung cancer patients, revealed potential correlations between salivary microbiome and immunocytochemistry markers used in clinical diagnostics, and provided proof that salivary microbiota can be an informative source for discovering non-invasive lung cancer biomarkers.

Integrative Bioinformatics Analysis Reveals Potential Long Non-Coding RNA Biomarkers and Analysis of Function in Non-Smoking Females with Lung Cancer

BackgroundLung cancer is the most lethal cancer worldwide. The aim of this study was to identify the tumor-related lncRNAs and explore their functions in female non-smokers with lung cancer.Material/MethodsThe gene expression microarray datasets GSE19804, GSE31210, and GSE31548 were downloaded from the Gene Expression Omnibus database. The differentially-expressed lncRNAs between non-smoking female lung cancer samples and non-tumor lung tissues were identified using GEO2R.ResultsIn total, 25, 40, and 15 differentially-expressed lncRNAs were obtained from GSE19804, GSE31210, and GSE31548 datasets (|logFC| >1, adj. P<0.05), respectively. Eight lncRNAs were screened out in all 3 datasets. Of these, 5 lncRNAs were up-regulated and 3 lncRNAs were down-regulated in lung cancer tissues compared to non-tumor lung tissues. Then, the target miRNAs of aberrantly expressed lncRNAs and target mRNAs corresponding to miRNAs were predicted. Subsequently, the ceRNA network with 8 key lncRNAs, 20 miRNAs, and 38 mRNAs were constructed. Functional and pathway enrichment analysis showed these target genes were mainly enriched in biological processes associated with protein binding, nucleus, metal ion binding, regulation of transcription from RNA polymerase II promoter, nucleic acid binding, cell differentiation, microRNAs in cancer, and the hippo signaling pathway. Survival analysis of these lncRNAs revealed that low LINC00968 (P=0.0067) and TBX5-AS1 (P=0.0028) expression were associated with unfavorable prognosis in never-smoking female lung cancer patients.ConclusionsThe present study promotes understanding of the molecular mechanism of the pathogenesis of non-smoking female lung cancer and provides potential biomarkers for diagnosis and treatment.

Association of PPP1R13L and CD3EAP polymorphisms with risk and survival of non-small cell lung cancer in Chinese non-smoking females

PPP1R13L and CD3EAP were confirmed to play important roles in transcription and apoptosis. SNPs in PPP1R13L and CD3EAP may be associated with lung cancer risk and survival. This study investigated the association of PPP1R13L rs1005165 and CD3EAP rs967591 with non-small cell lung cancer (NSCLC) risk and survival in Chinese non-smoking females. 442 NSCLC cases and 480 cancer-free controls were conducted in the case-control study, and 283 cases were in cohort study. Genotype was determined by Taqman real-time PCR. The statistical analyses were performed by SPSS 22.0 software. We found that rs1005165 and rs967591 were significantly associated with NSCLC risk in Chinese non-smoking females. For rs1005165, compared with homozygous wild CC genotype, carriers of CT or TT genotype had lower risk of NSCLC (adjusted ORs were 0.675 and 0.713, 95% CI were 0.461-0.988 and 0.525-0.968, respectively), adjusted OR for dominant model was 0.702, 95% CI was 0.526-0.937. For rs967591, AA genotype (adjusted OR = 0.721, 95% CI = 0.532-0.978) and at least one A allele (GA+AA) (adjusted OR = 0.716, 95% CI = 0.536-0.956) were significantly correlated with lower risk of NSCLC, compared with GG genotype. But we didn’t find correlation between the two SNPs and survival time in Chinese non-smoking NSCLC females. In general, we found PPP1R13L rs1005165 and CD3EAP rs967591 might be associated with lower NSCLC risk in Chinese non-smoking females, but no significant relationship was found with NSCLC survival.

MiR-196a2 and lung cancer in Chinese non-smoking females: a genetic association study and expression analysis.

BackgroundThe common polymorphism rs11614913 in miR-196a2 might be associated with lung cancer risk for non-smoking females in northeast China.MethodsThe genotypes of rs11614913 in miR-196a2 were determined by a case-control study including 1003 patients with lung cancer and 1003 healthy controls. The tissues were detected to assess the miRNA expression. Secondary structures of miR-196a2 were predicted.ResultsThere was a significant association between miR-196a2 rs11614913 and lung cancer risk in Chinese non-smoking females. Individuals carrying TC or CC genotype had increased risk of lung cancer compared with TT genotype (adjusted risks were 1.63 and 1.67). The C allele was associated with a higher risk of lung cancer with a significant risk of 1.27. The similar significant results were also found in lung adenocarcinoma. There was a significant association between miR-196a2 expression and lung cancer risk (t=2.594, P=0.012). The relative expression of miR-196a2 was significantly higher for CC genotype comparing with the CT or TT genotype in tumor tissues (P values were all 0.003). The optimal free energies were different for T allele and C allele.ConclusionsThe polymorphism rs11614913 in miR-196a2 may be associated with lung cancer risks in Chinese non-smoking females through affecting miR-196a2 expression and secondary structure.

Estrogen and cigarette sidestream smoke particulate matter exhibit ERα-dependent tumor-promoting effects in lung adenocarcinoma cells.

Estrogen and secondhand smoke are key risk factors for nonsmoking female lung cancer patients who frequently have lung adenocarcinoma and show tumor estrogen receptor α (ERα) expression. We speculated that estrogen and secondhand smoke might cause harmful effects via ERα signaling. Our results showed that 17β-estradiol (E2), the primary form of endogenous estrogen, exacerbated proliferation, migration, and granzyme B resistance of lung adenocarcinoma cells in an ERα-dependent manner. Cigarette sidestream smoke particulate matter (CSSP), the major component of secondhand smoke, could activate ERα activity dose dependently in human lung adenocarcinoma cells. The estrogenic activity of CSSP was abolished by an ERα-selective antagonist. CSSP regulated the nuclear entry, phosphorylation, and turnover of ERα similarly to E2. Furthermore, CSSP enhanced E2-stimulated ERα activity and Ser118 phosphorylation even when ERα became saturated with E2. Activation of ERα by CSSP required GSK3β activity, but not involving polycyclic aromatic hydrocarbons, reactive oxygen species, calcium, epidermal growth factor receptor, and PI3K/Akt. Although CSSP possessed cytotoxicity, ERα-expressing cells grew and migrated faster than nonexpressing cells on recovery from CSSP exposure as observed in E2-pretreated cells. Knockdown of ERα by siRNA diminished E2- and CSSP-stimulated cell migration. Twenty-one genes, including SERPINB9, were identified to be upregulated by both E2 and CSSP via ERα. Increased SERPINB9 expression was accompanied with increased resistance to granzyme B-mediated apoptosis. This study demonstrates that estrogen has ERα-dependent tumor-promoting activity. CSSP acts like estrogen and shows a potential to enhance estrogen-induced ERα action.

Single nucleotide polymorphism rs3124599 in Notch1 is associated with the risk of lung cancer in northeast Chinese non-smoking females.

Lung cancer is one of the most common cancers and the main cause of cancer-related deaths. Notch1 might play a part in tumorigenesis of lung cancer. Here we explored the relationship of three SNPs (rs3124599, rs3124607 and rs3124594) in Notch1 with the risk and the survival of lung cancer in non-smoking females, including 556 cases and 395 controls. Chi-square tests, logistic regression analysis and crossover analysis were conducted to estimate the association between SNPs and the risk of lung cancer and the interaction between SNPs and environmental exposure. Survival analysis was conducted to explore the association between SNPs and survival of lung cancer. The results demonstrated that the polymorphism of rs3124599 was associated with the susceptibility of lung cancer in recessive model (AA+AG vs. GG). Compared to the those with AA or AG genotype, individuals with GG genotype had a 1.562-fold increased risk of lung cancer (P = 0.023, OR = 1.562, 95% CI = 1.062-2.297). In stratified analysis, the GG genotype of rs3124599 would increase the risk of small cell lung cancer (SCLC) (P = 0.011, OR = 2.167, 95% CI = 1.193-3.396). However, no significant interaction between rs3124599 and cooking oil fume exposure was observed either in addictive model or multiplicative model. The results of survival analysis showed there was no significant association between SNPs and prognosis of lung cancer (P = 0.949 for rs3124599, P = 0.508 for rs3124607, P = 0.884 for rs3124594). Our study might indicate that rs312599 in Notch1 may be a novel biomarker for SCLC risk in Chinese non-smoking females

MiR-146a polymorphism correlates with lung cancer risk in Chinese nonsmoking females.

This study provides evidence that the common rs2910164 polymorphism in miR-146a strongly correlates with lung cancer risk in nonsmoking females in northeast China. The genotypes of miR-146a rs2910164 were determined in 1131 patients with lung cancer and 1003 healthy control subjects. Tissue samples were used to evaluate the association between miRNA expression and lung cancer risk as well as the correlation between rs2910164 genotypes and miR-146a expression. The secondary structures of the wild-type and variant miR-146a sequences were predicted, and luciferase-based target assays were used to test whether miR-146a bound to tumor necrosis factor receptor associated factor 6 (TRAF6) mRNA. Individuals carrying heterozygous CG genotype of miR-146a rs2910164 had less risk of lung cancer than those carrying homozygous wild CC genotype (OR = 0.76, 95% CI = 0.60-0.98, P = 0.032). We found no significant association between miR-146a expression and lung cancer risk. MiR-146a expression differed in those carrying the CC genotype as compared with the CG or the GG genotype (P = 0.032 and 0.001), and the secondary structure of the C allele differed slightly from the G allele. Significantly lower levels of luciferase activity were observed when the TRAF6 3′UTR was cotransfected with miR-146a-3p carrying the rs2910164 C allele (P = 0.001). Thus, miR-146a rs2910164 polymorphism may influence susceptibility to lung cancer in Chinese nonsmoking females through targeting TRAF6.

Polymorphisms in miR-135a-2, miR-219-2 and miR-211 as well as their interaction with cooking oil fume exposure on the risk of lung cancer in Chinese nonsmoking females: a case-control study.

BackgroundThe associations between microRNAs and lung cancer have received increasing attention. This study assess the association between polymorphisms in miR-135a-2, miR-219-2 and miR-211 genes and the risk of lung cancer, as well as the gene–environment interaction between these polymorphisms and cooking oil fume exposure.MethodsA case–control study featuring 268 cases and 266 controls was conducted. The associations of miR-135a-2 rs10459194, miR-219-2 rs10988341 and miR-211 rs1514035 polymorphisms with the risk of lung cancer were analyzed. The gene–environment interactions were also reported on both additive and multiplicative scales.ResultsThere were no statistically significant associations between the single-nucleotide polymorphisms (SNPs) and lung cancer or lung adenocarcinoma. The individuals with both a risk genotype of miRNA SNPs and exposure to a risk factor (cooking oil fumes) were at higher risk of lung cancer than those with only one of these two risk factors (odd ratios of 2.208, 1.285 and 1.813 for miR-135a-2 rs10459194; 2.164, 1.209 and 1.806 for miR-219-2 rs10988341; and 2.122, 1.146 and 1.725 for miR-211 rs1514035, respectively). However, the measures of biological interaction indicate that there was no such interaction between the three SNPs and exposure to cooking oil fumes on an additive scale. Logistic regression models also suggested that the gene–environment interactions were not statistically significant on a multiplicative scale.ConclusionsThere were no significant associations between the polymorphisms in miRNAs (miR-26a-1 rs7372209, miR-605 rs2043556 and miR-16-1 rs1022960) and the risk of lung cancer in the Chinese nonsmoking female population. The interactions between these polymorphisms in miRNAs and cooking oil fume exposure were also not statistically significant.

Abstract 2568: Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women

Abstract Background: The incidence rates of lung cancer among never-smoking females in some parts of East Asia are among the highest in the world. Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk including 3q28, 5p15.33, 6p21.32, 6q22.2, 10q25.2 and 17q24.3. This study aims to discover additional lung cancer susceptibility loci among never-smoking Asian females. Methods: We imputed data from four GWAS of Asian non-smoking female lung cancer (6,877 cases and 6,277 controls) using the 1,000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5,878 cases and 7,046 controls) for potential replication. Results: In our meta-analysis, three new loci achieved genome-wide significance, marked by the single nucleotide polymorphisms rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10-13), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 ×10-10), and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 ×10-9). Conclusions: We identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia. These findings merit follow-up to understand their biological underpinnings and potential interactions with environmental exposures. Citation Format: Qing Lan, Zhaoming Wang, Wei Jie Seow, Kouya Shiraishi, Hongbing Shen, Chao A. Hsiung, Keitaro Matsuo, Jie Liu, Kexin Chen, Taiki Yamji, Yang Yang, I-Shou Chang, Chen Wu, Meredith Yeager, Takashi Kohno, Wei Zheng, Xiao-Ou Shu, Pan-Chyr Yang, Tangchun Wu, Dongxin Lin, Baosen Zhou, Jinming Yu, Michiaki Kubo, Stephen J. Chanock, Nathaniel Rothman. Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2568.

Association between polymorphisms in pre-miRNA genes and risk of lung cancer in a Chinese non-smoking female population

BackgroundMicroRNAs play important roles in the development of human chronic diseases including lung cancer. This is the first case-control study of lung cancer in a non-smoking female population in northeast China, to evaluate the roles of the polymorphisms in pre-miRNAs on risk of lung cancer. MethodsThe genotypes of six polymorphisms in miRNAs were determined in 575 patients with lung cancer and 608 healthy controls who were frequency matched for age. ResultsFor miR-146a rs2910164, individuals carrying heterozygous CG or homozygous GG genotype had decreased risks of lung cancer compared with those carrying homozygous wild CC genotype (adjusted odds ratios were 0.76 and 0.64, 95% confidence intervals were 0.59–0.99 and 0.46–0.90, P values were 0.039 and 0.010, respectively). G allele of rs2910164 was associated with a lower risk of lung cancer with a significant odds ratio of 0.80. MiR-423 rs6505162CA or AA genotype was associated with significantly decreased risk for lung cancer compared to CC genotype (adjusted odds ratios were 0.77 and 0.54). The significant result was also found in the allele model with odds ratio of 0.75. However, miR-196a2 rs11614913, miR-30c-1 rs928508, miR-608 rs4919510 and miR-27a rs895819 polymorphisms were not significantly associated with lung cancer risks in any models. The similar results were also found in lung adenocarcinoma patients. ConclusionsThese findings suggest that miR-146a rs2910164C>G and miR-423 rs6505162C>A polymorphisms may contribute to genetic susceptibility to lung cancer and lung adenocarcinoma in Chinese non-smoking females.

Meta-analysis of genome-wide association studies identifies multiple lung cancer susceptibility loci in never-smoking Asian women.

Genome-wide association studies (GWAS) of lung cancer in Asian never-smoking women have previously identified six susceptibility loci associated with lung cancer risk. To further discover new susceptibility loci, we imputed data from four GWAS of Asian non-smoking female lung cancer (6877 cases and 6277 controls) using the 1000 Genomes Project (Phase 1 Release 3) data as the reference and genotyped additional samples (5878 cases and 7046 controls) for possible replication. In our meta-analysis, three new loci achieved genome-wide significance, marked by single nucleotide polymorphism (SNP) rs7741164 at 6p21.1 (per-allele odds ratio (OR) = 1.17; P = 5.8 × 10(-13)), rs72658409 at 9p21.3 (per-allele OR = 0.77; P = 1.41 × 10(-10)) and rs11610143 at 12q13.13 (per-allele OR = 0.89; P = 4.96 × 10(-9)). These findings identified new genetic susceptibility alleles for lung cancer in never-smoking women in Asia and merit follow-up to understand their biological underpinnings.

Polymorphisms in pre-miRNA genes and cooking oil fume exposure as well as their interaction on the risk of lung cancer in a Chinese nonsmoking female population

BackgroundMicroRNAs (miRNAs) are suggested to be very important in the development of lung cancer. This study assesses the association between polymorphisms in miRNA-related (miR)-26a-1, miR-605, and miR-16-1 genes and risk of lung cancer, as well as the effect of gene–environment interaction between miRNA polymorphisms and cooking fume exposure on lung cancer.MethodsA case–control study including 268 diagnosed nonsmoking female lung cancer patients and 266 nonsmoking female controls was carried out. Three miRNA polymorphisms (miR-26a-1 rs7372209, miR-605 rs2043556, and miR-16-1 rs1022960) were analyzed. Both additive and multiplicative interactions were assessed.ResultsMiR-16-1 rs1022960 may be associated with the risk of lung cancer. Carriers with TT genotype of miR-16-1 rs1022960 were observed to have a decreased risk of lung cancer compared with CC and CT genotype carriers (odds ratio =0.550, 95% confidence interval =0.308–0.983, P=0.044). MiR-26a-1 rs7372209 and miR-605 rs2043556 showed no statistically significant associations with lung cancer risk. There were no significant associations between the three single nucleotide polymorphisms and lung adenocarcinoma. People with exposure to both risk genotypes of miR-26a-1 rs7372209 and cooking oil fumes were more likely to develop lung cancer than those with only genetic risk factor or cooking oil fumes (odds ratios were 2.136, 1.255, and 1.730, respectively). The measures of biological interaction and logistic models indicate that gene–environment interactions were not statistically significant on additive scale or multiplicative scale.ConclusionMiR-16-1 rs1022960 may be associated with the risk of lung cancer in a Chinese nonsmoking female population. The interactions between miRNA polymorphisms (miR-26a-1 rs7372209, miR-605 rs2043556, and miR-16-1 rs1022960) and cooking oil fumes were not statistically significant.

Comprehensive analysis of genes, pathways, and TFs in nonsmoking Taiwan females with lung cancer

ABSTRACTPurpose: The aim of this study was to investigate the molecular mechanism of lung cancer among nonsmoking Taiwan females. Materials and methods: By using the GSE19804 microarray data accessible from Gene Expression Omnibus (GEO) database, we identified differentially expressed genes (DEGs) between nonsmoking female lung cancer patients and healthy controls (!logFC! >1.5 and p-value < 0.05). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway and Gene ontology (GO) enrichment analysis was performed using Database for Annotation, Visualization and Integrated Discovery (DAVID). The Search Tool for the Retrieval of Interacting Genes (STRING) tool was utilized to build a protein–protein interaction (PPI) network, followed by the construction of a transcriptional regulatory network based on Transcription factor (TRANSFAC) database. Results: As a result, 320 DEGs were identified between nonsmoking female patients with lung cancer and healthy controls. Pathway enrichment analysis showed significantly enriched pathways such as extracellular matrix (ECM)-receptor interaction and peroxisome proliferator-activated receptor (PPAR) signaling pathway, both of which were enriched with genes COL11A1 (encoding collagen XI alpha-1 chain protein), COL1A1, cluster of differentiation 36(CD36). GO enrichment analysis found that DEGs were significantly related to chemotaxis, vasculature development and cell adhesion GO terms. IL-6 was the node of the PPI network. Critical transcription factors (TFs) including CCAAT/enhancer-binding protein delta (CEBPD) and Rel/NF-κB were also identified. Conclusions: Our study revealed that ECM-receptor interaction, PPAR signaling pathways, and important biomolecules including COL11A1, COL1A1, CD36, IL-6, CEBPD, and Rel/NF-κB might be involved in lung cancer. This study might pave the way for the development and application of targeted therapeutics of lung cancer irrelevant to smoking.

Genetic polymorphisms of TERT and CLPTM1L, cooking oil fume exposure, and risk of lung cancer: a case-control study in a Chinese non-smoking female population.

Genetic polymorphisms of telomerase reverse transcriptase (TERT) and cleft lip and palate transmembrane 1-like (CLPTM1L) genes in chromosome 5p15.33 region were previously identified to influence the risks of lung cancer. This study aimed to investigate the association between polymorphisms in TERT and CLPTM1L genes with the risk of lung cancer, as well as the interaction of the polymorphisms and the environmental risk factors in Chinese non-smoking females. A hospital-based case-control study of 524 cases and 524 controls was conducted. Two polymorphisms were determined by Taqman allelic discrimination method. The statistical analyses were performed mostly with SPSS. This study showed that the individuals with the TG or GG genotypes of TERT polymorphism (rs2736100) were at an increased risk for lung cancer compared with those carrying the TT genotype in Chinese non-smoking females [adjusted odds ratios (ORs) were 1.44 and 1.85, 95 % confidence intervals (CIs) were 1.09-1.90 and 1.29-2.65, respectively]. The stratified analysis suggested that increased risks were more pronounced in lung adenocarcinoma (corresponding ORs were 1.71 and 2.30, 95 % CIs were 1.25-2.35 and 1.54-3.43). Our results showed that exposure to cooking oil fume was associated with increased risk of lung cancer in Chinese non-smoking females (adjusted ORs 1.59, 95 % CI 1.13-2.23). However, we did not observe a significant interaction of cooking oil fume and TERT polymorphism on lung cancer among Chinese non-smoking females. TERT polymorphism (rs2736100) might be a genetic susceptibility factor for lung cancer in non-smoking females in China.

Human Papillomavirus Up-Regulates MMP-2 and MMP-9 Expression and Activity by Inducing Interleukin-8 in Lung Adenocarcinomas

Human papillomavirus (HPV) infection is associated with non-smoking female lung cancer. Our previous report demonstrated that HPV 16 promotes lung tumor cell progression by up-regulating interleukin-17 (IL-17). IL-17 and its downstream signaling mediator, interleukin-8 (IL-8), have been implicated to modulate a variety of pro-angiogenic factors and play important roles in tumor angiogenesis and metastasis. Accordingly, we hypothesized that HPV infection may potentiate tumorigenic and metastatic characteristics of the infected cells through IL-8. The goal of the present study was to determine whether HPV infection in lung adenocarcinoma cells can promote the expression of IL-8 and metalloproteinases (MMPs) to make the transformed cells equipped with angiogenic and metastatic characteristics. The expression of IL-8 and MMPs in HPV 16 E6-transfected H1299 cells was analyzed to examine the hypothesis. HPV 16 E6 up-regulates pro-angiogenic MMP-2 and MMP-9 through inducing IL-8 expression in lung cancer cells. The results indicate that, in addition to cell proliferation-related machinery, HPV infection promotes the expression and activities of angiogenic and metastatic molecules in lung adenocarcinoma cells. The cytokines induced by HPV infection may work together to confer the malignant and tumorigenic potentials on the infected cells by promoting machineries of growth, angiogenic and metastatic characteristics.