Risk Of Non-small Cell Lung Cancer Research Articles

APOBEC3B deletion polymorphism and lung cancer risk in the southern Chinese population.

BackgroundApproximately 80–85% of lung cancer is the non-small cell lung cancer (NSCLC) subtype, which ranks as the leading cause of cancer deaths worldwide. APOBEC3B (A3B) was reported to be a key source of mutations in NSCLC. However, the role of the A3B deletion polymorphism in the etiology of NSCLC has not been well-documented.MethodsA case-control study with 317 NSCLC patients and 334 healthy controls was conducted to explore the association between the A3B deletion polymorphism and the risk of NSCLC. The unconditional logistic regression model was performed to calculate the odds ratio (OR) and the 95% confidence interval (CI), and the confounding factors were adjusted, including age, gender, and smoking status, to estimate the risk. An analysis of gene-environment interactions was performed using multifactor dimensionality reduction (MDR) software.ResultsWe found that the del/del genotype of A3B deletion significantly increased NSCLC risk. Compared with individuals carrying the ins/ins genotype of A3B deletion, individuals with the del/del genotype had a 2.36 times increased risk of developing NSCLC after adjusting for confounding factors (OR =2.71, 95% CI: 1.67–4.42, P<0.001). A 3-factor gene-environment (A3B deletion, gender, and smoking) interaction model was found for NSCLC (OR =4.407, 95% CI: 1.174–16.549, P=0.028).ConclusionsWe propose that the A3B deletion polymorphism can increase the risk of developing NSCLC, and their interactions with gender and smoking may contribute to the risk of NSCLC in the southern Chinese population.

Association Between Triglyceride Glucose Index and Non-Small Cell Lung Cancer Risk in Chinese Population.

BackgroundNumerous studies showed that insulin resistance (IR) was associated with cancer risk. However, few studies investigated the relationship between IR and non-small cell lung cancer (NSCLC). The aim of this study is to explore the association of triglyceride glucose (TyG) index, a simple surrogate marker of IR, with NSCLC risk.Methods791 histologically confirmed NSCLC cases and 787 controls were enrolled in the present study. Fasting blood glucose and triglyceride were measured. The TyG index was calculated as ln [fasting triglycerides (mg/dl) ×fasting glucose (mg/dl)/2]. Logistic regression analysis was performed to estimate the relationship between NSCLC risk and the TyG index.ResultsThe TyG index was significantly higher in patients with NSCLC than that in controls (8.42 ± 0.55 vs 8.00 ± 0.45, P < 0.01). Logistic regression analysis showed that the TyG index (OR = 3.651, 95%CI 2.461–5.417, P < 0.001) was independently associated with NSCLC risk after adjusting for conventional risk factors. In addition, a continuous rise in the incidence of NSCLC was observed along the tertiles of the TyG index (29.4 vs 53.8 vs 67.2%, P < 0.001). However, there were no differences of the TyG index in different pathological or TNM stages. In receiver operating characteristic (ROC) curve analysis, the optimal cut-off level for the TyG index to predict incident NSCLC was 8.18, and the area under the ROC curve (AUROC) was 0.713(95% CI 0.688–0.738).ConclusionsThe TyG index is significantly correlated with NSCLC risk, and it may be suitable as a predictor for NSCLC.

Association between sex hormones regulation-related SNP rs12233719 and lung cancer risk among never-smoking Chinese women.

BackgroundThe mechanism of rapidly increased non‐small cell lung cancer (NSCLC) among never‐smoking Chinese women has not been elucidated. Ovarian sex steroid hormones have been suggested to counteract lung cancer development, and sex hormone‐binding globulin (SHBG) is essential in sex hormones regulation. This study aims to exploring single nucleotide polymorphisms (SNPs) in genomic regions associated with SHBG concentrations that contributed to never‐smoking female NSCLC.MethodsCandidate genes were selected by a genome‐wide association (GWAS) meta‐analysis and gene expression profiles of never‐smoking NSCLC of Chinese women. The candidate SNPs limited to common minor allele frequency (MAF), missense variant, ethnic heterogeneous distribution, and SNPs were genotyped using the TaqMan method. A two‐stage case‐control design was adopted for exploration and validation of associations between candidate SNPs and risk of NSCLC. All participants were never‐smoking Chinese women. Chi‐square test and multivariate logistic regression were applied.ResultsBeginning with 12 genomic regions associated with circulating SHBG concentrations and gene expression profiles from never‐smoking NSCLC in Chinese women, candidate SNP rs12233719 and rs7439366 both located in candidate gene UGT2B7, which may be related to circulating SHBG concentrations and cancer risk, were identified. A two‐stage case‐control study was conducted in Shenyang and Tianjin represented as the training stage and validation stage, respectively. Under the dominant model, compared to individuals with the wild G/G genotype, the adjusted OR of those with the T allele was 1.58 (95% CI: 1.15–2.16) in Chinese Shenyang training set, and was 1.49 (95% CI: 1.02–2.18) in Chinese Tianjin validation set, both accompanied with a significant trend relationship consistently. UGT2B7 was upregulated in female NSCLC patients’ tumor tissues and was associated with a poor prognosis in NSCLC.ConclusionOur findings indicated that a sex hormones regulation‐related SNP rs12233719 was associated with never‐smoking female lung cancer risk, which might partially explain NSCLC‐susceptibility in Chinese women.

Association between microRNA-146a, -499a and -196a-2 SNPs and non-small cell lung cancer: a case-control study involving 2249 subjects.

MicroRNA (miR) acts as a negative regulator of gene expression. Many literatures have suggested that miRs may be involved in the process of cell proliferation, inflammation, oxidative stress, energy metabolism and epithelial–mesenchymal transition. Thus, miRs may be implicated in the occurrence of non-small cell lung cancer (NSCLC). In the current investigation, we included 2249 subjects (1193 NSCLC patients and 1056 controls) and designed a study to identify the relationship of miR-146a rs2910164 C/G, -499a rs3746444 A/G and -196a-2 rs11614913 T/C with the risk of NSCLC. The risk factors (e.g., body mass index (BMI), sex, smoking, drinking and age) was used to adjust the odds ratios (ORs) and 95% confidence intervals (CIs). After conducting a power value assessment, we did not confirm that the miR-single nucleotide polymorphisms (SNPs) genotypic distributions were different in NSCLC cases and controls. However, the association of miR-196a-2 rs11614913 with a decreased risk of NSCLC was identified in the female subgroup (adjusted P=0.005, power = 0.809 for TC vs. TT, and adjusted P=0.004, power = 0.849 for CC/TC vs. TT). In addition, gene–gene interaction analysis showed that rs11614913 TC/3746444 AA and rs11614913 CC/rs3746444 AA could also reduce the susceptibility to NSCLC (rs11614913 TC/rs3746444 AA vs. rs11614913 TT/rs3746444 AA, P=0.001, power = 0.912 and rs11614913 CC/rs3746444 AA vs. rs11614913 TT/rs3746444 AA, P=0.003, power = 0.836). In conclusion, in overall comparisons, we did not confirm that the rs2910164, rs3746444, and rs11614913 SNPs genotypic distributions were different in NSCLC cases and controls. However, this case–control study demonstrates that miR-196a-2 rs11614913 may be a protective factor for the development of NSCLC among female patients.

Association of BTLA Polymorphisms with Susceptibility to Non-Small-Cell Lung Cancer in the Chinese Population.

Studies have reported that B- and T-lymphocyte attenuator (BTLA) polymorphisms may be associated with the risk to different cancers. However, the correlation between those variations and non-small-cell lung cancer (NSCLC) is still unclear. A total of 1,003 NSCLC patients and 901 noncancer controls were recruited in the study, to confirm the association of variations in BTLA gene with the risk of NSCLC. The SNPscan™ genotyping assay was used to obtain the genotypes of the four BTLA polymorphisms (BTLA rs1982809 G>A, rs16859629 T>C, rs2171513 G>A, and rs3112270 A>G). It was found that BTLA rs1982809 polymorphism reduced the risk of NSCLC (GA vs. GG: adjusted odds ratio (OR) = 0.81, 95%confidence interval (CI) = 0.66‐0.99, and P = 0.043). However, the BTLA rs16859629, rs2171513, and rs3112270 polymorphisms showed no significant association between NSCLC patients and controls in overall comparison. In subgroup analyses, we found that BTLA rs1982809 polymorphism reduced the risk of NSCLC (nonsquamous cell carcinoma: GA vs. GG: adjusted OR = 0.79, 95%CI = 0.64‐0.97, and P = 0.026; AA/GA vs. GG: adjusted OR = 0.81, 95%CI = 0.66‐0.99, and P = 0.037; ≥59 years: GA vs. GG: P = 0.036; never alcohol consumption: GA vs. GG: P = 0.013; GA/AA vs. GG: P = 0.016; body mass index (BMI) ≥ 24 kg/m2: GA vs. GG: P = 0.030; GA/AA vs. GG: P = 0.041). The BTLA rs16859629 polymorphism increased the risk of the development of squamous cell carcinoma (CC vs. TT: adjusted OR = 9.85, 95%CI = 1.37‐71.03, and P = 0.023; CC vs. TT/TC: adjusted OR = 9.55, 95%CI = 1.32‐68.66, and P = 0.025). Taken together, the findings of the present suggest that BTLA rs1982809 and rs16859629 polymorphisms may influence the susceptibility to NSCLC in the Chinese population.

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.

Effect of Body Weight and Other Metabolic Factors on Risk of Non-Small Cell Lung Cancer among Veterans with HIV and a History of Smoking.

Simple SummaryAmong people living with HIV (PWH), there has been an increasing incidence of non-small cell lung cancer (NSCLC) and metabolic abnormalities, such as diabetes and high cholesterol, which affect the risk of NSCLC. In this article, we evaluate which metabolic risk factors increase the risk of NSCLC among PWH who smoke. Through a retrospective study that includes 33,351 veterans, we found that the risk of NSCLC was lower in well-controlled PWH (1.46 vs. 2.06/1000 patient/year [PY]). Metabolic factors associated with higher NSCLC risk included lower body weight at HIV diagnosis and a remote history of involuntary weight loss in PWH regardless of whether they had a well-controlled infection or not. Lower HDL and triglyceride levels increased the risk of NSCLC only in non-well-controlled smokers. Our results suggest these factors may be important to consider in targeting surveillance and for early identification of NSCLC in PWH smokers.Among people living with HIV (PWH), there has been an increasing incidence of non-small cell lung cancer (NSCLC) and metabolic abnormalities, including dyslipidemia, which can modulate NSCLC risk. In this article, we evaluate which metabolic risk factors are associated with incident risk among PWH who smoke. This is done through a retrospective cohort study, using data of HIV+ veterans who smoke from the nationwide Veterans Affairs (VA) healthcare system. Data on diagnostic codes, medication, and laboratory values of 33,351 veterans were obtained using the VA’s Corporate Data Warehouse and Central Cancer Registry. We calculated NSCLC incidence and utilized Cox regression to determine metabolic factors associated with NSCLC risk. HIV+ cohort was 97.4% male; median age = 47 years and 20,050 (60.1%) well-controlled (≥80% follow-up time undetectable viral load). Crude incidence rates were lower in well-controlled PWH (1.46 vs. 2.06/1000 PY). Metabolic factors associated with incident NSCLC risk included lower BMI at HIV diagnosis and cachexia history in both groups, while HDL and triglycerides were significant in non-well-controlled smokers only. Our findings that lower BMI at HIV diagnosis, history of cachexia among individuals with well-controlled HIV, and cachexia presence at diagnosis are associated with increased risk of developing NSCLC in PWH with a history of smoking have important implications.

Heart substructural dosimetric parameters and risk of cardiac events after definitive chemoradiotherapy for stage III non-small cell lung cancer

IntroductionWe evaluated the incidence of cardiac events after chemoradiotherapy in patients with stage III non-small cell lung cancer (NSCLC) based on baseline cardiovascular risk and the heart substructures’ radiation dose. MethodsFrom 2008 to 2018, the cardiac events of 258 patients with stage III NSCLC who received definitive chemoradiotherapy were reviewed. The 10-year cardiovascular risk was calculated using the Atherosclerotic Cardiovascular Disease (ASCVD) scoring system. Dose-volume histograms were estimated for each cardiac chamber. A multivariate competing-risk regression analysis was conducted to assess each cardiac event’s subhazard function (SHR). ResultsThe median follow-up was 27.5 months overall and 38.9 months for survivors. Among the 179 deaths, none was definitely related to cardiac conditions. Altogether, 32 cardiovascular events affected 27 patients (10.5%) after chemoradiotherapy. Ten were major cardiac adverse events, including heart failure (N = 6) and acute coronary syndrome (ACS, N = 4). Most cardiovascular events were related to well-known risk factors. However, the volume percentage of the left ventricle (LV) receiving 60 Gy (LV V60) > 0 was significantly associated with ACS (SHR = 9.49, 95% CI = 1.28–70.53, P = 0.028). In patients with high cardiovascular risk (ASCVD score > 7.5%), LV V60 > 0% remained a negative ACS prognostic factor (P = 0.003). Meanwhile, in patients with low cardiovascular risk, the LV radiation dose was not associated with ACS events (P = 0.242). ConclusionsA high LV radiation dose could increase ACS events in patients with stage III NSCLC and high cardiovascular risk. Pre-treatment cardiac risk evaluation and individualized surveillance may help prevent cardiac events after chemoradiotherapy.

S0398 The Association Between Gastroesophageal Reflux Disease and Non-Small Cell Lung Cancer: A Retrospective Case Control Study

INTRODUCTION: Lung cancer is a leading cause of mortality in the USA. Non-small cell lung cancer (NSCLC) contributes to 85% of all lung cancers. It is the most prevalent subtype amongst non-smokers and its incidence has risen in the last 20 years. Gastroesophageal reflux disease (GERD) has been reported to be associated with several lung pathologies, namely idiopathic pulmonary fibrosis, and asthma. We aimed to investigate the association between GERD and NSCLC by performing a retrospective, multicentered, case-control study. This is the first study of this nature to be carried out in the USA. METHODS: Data was retrieved from 17 Northwell health care facilities in the New York area between years, 2010–2018. Inclusion criteria were patients >18 years of age with NSCLC (large cell, adenocarcinoma, and squamous cell) and were appropriately matched with controls based on age, gender, weight, co-morbidities, and medication use. Our exposure group had a diagnosis of GERD based on ICD-9/10 codes, endoscopic, and/or histological evidence. We excluded patients with secondary lung cancers, esophageal adenocarcinoma, or other primary malignancies, Barrett’s esophagus, as well as smokers. Statistical analysis was carried out using SAS (SAS Institute, NC, USA). Logistic regression was conducted to determine the adjusted odds ratio (OR) and corresponding 95% confidence interval (CI) for the association between NSCLC and GERD. RESULTS: A total of 1,083 subjects were included in our study: 543 (50%) patients were diagnosed with NSCLC. In this population, GERD was twice as prevalent when compared to controls (20.4% vs. 11.6%, P < 0.001). Multivariate analysis demonstrated that GERD was associated with a higher risk of NSCLC compared to matched controls (OR = 1.86, 95% CI = 1.26–2.73). GERD patients treated with either antihistamines or proton pump inhibitors did not demonstrate an overall reduced risk of NSCLC (OR = 1.01, 95% CI = 0.48–2.12). Other independent risk predictors of NSCLC are summarized in Table 2. CONCLUSION: Our study demonstrates that GERD might be associated with a higher risk NSCLC, irrespective of the treatment of GERD. We postulate that GERD patients may suffer from chronic micro-aspirations leading to a prolonged inflammatory state within the lung parenchyma triggering proliferative signaling pathways leading to malignant transformation. Prospective trials are needed to further explore this relationship and clarify the role of GERD therapy.Table 1.: Baseline demographic characteristics of patients with Non-small cell lung cancer (NSCLC) and controlsTable 2.: Multivariate logistic regression analysis for the risk predictors of Non-small cell lung cancerFigure 1.: Forest plot of odds ratio (OR) values according to the independent risk predictors of non-small cell lung cancer.

Comprehensive functional annotation of susceptibility variants identifies genetic heterogeneity between lung adenocarcinoma and squamous cell carcinoma.

Although genome-wide association studies have identified more than eighty genetic variants associated with non-small cell lung cancer (NSCLC) risk, biological mechanisms of these variants remain largely unknown. By integrating a large-scale genotype data of 15 581 lung adenocarcinoma (AD) cases, 8350 squamous cell carcinoma (SqCC) cases, and 27 355 controls, as well as multiple transcriptome and epigenomic databases, we conducted histology-specific meta-analyses and functional annotations of both reported and novel susceptibility variants. We identified 3064 credible risk variants for NSCLC, which were overrepresented in enhancer-like and promoter-like histone modification peaks as well as DNase I hypersensitive sites. Transcription factor enrichment analysis revealed that USF1 was AD-specific while CREB1 was SqCC-specific. Functional annotation and gene-based analysis implicated 894 target genes, including 274 specifics for AD and 123 for SqCC, which were overrepresented in somatic driver genes (ER = 1.95, P = 0.005). Pathway enrichment analysis and Gene-Set Enrichment Analysis revealed that AD genes were primarily involved in immune-related pathways, while SqCC genes were homologous recombination deficiency related. Our results illustrate the molecular basis of both well-studied and new susceptibility loci of NSCLC, providing not only novel insights into the genetic heterogeneity between AD and SqCC but also a set of plausible gene targets for post-GWAS functional experiments.

Genetic variant rs2494938 of LRFN2 gene is associated with non-small cell lung cancer risk in North-Indian population.

Various Genome-wide association studies (GWAS) have reported the association of variant rs2494938 with lung cancer. However, genetic association of LRFN2 genetic variation with non-small cell lung cancer (NSCLC) in North Indian population remained unexplored. We conducted a case-control association study using TaqMan-based chemistry in which a total of 619 individuals, 189 NSCLC cases and 430 controls, were genotyped to explore the association of rs2494938 genetic variant of the LRFN2 gene with NSCLC patients from North India. The allele 'G' (risk allele) of the genetic variant rs2494938 was significantly associated with the NSCLC [OR = 1.51 (1.18-1.93 at 95% CI); p value = 0.0009]. Genetic association was also explored by applying different genetic models (Dominant, Additive). These results suggest that rs2494938 polymorphism of the LRFN2 gene is a risk factor in the North Indian populations to develop NSCLC. The LD (Linkage Disequilibrium) plot demonstrates the variant and its LD SNPs (r 2 > 0.8) and the variant has direct regulatory effect, which could affect the overall physiology of the gene. These findings could be used as diagnostic and prognostic markers in clinical studies of lung cancer patients in North Indian population groups. The present study also provides an important evidence on the genetic etiology of NSCLC in North Indian populations and further expounds GWAS findings on the role of LRFN2 in lung cancer risk. This study provides the holistic view about the non-small cell lung cancer in Jammu and Kashmir, North Indian population and it can be a hallmark of cancer if verified on a very large sample size (cohort).

A SNP-mediated lncRNA (LOC146880) and microRNA (miR-539-5p) interaction and its potential impact on the NSCLC risk

BackgroundMany cancer-associated single nucleotide polymorphisms (SNPs) are located in the genomic regions of long non-coding RNAs (lncRNAs). Mechanisms of these SNPs in connection to cancer risk are not fully understood.MethodsAssociation of SNP (rs140618127) in lncRNA LOC146880 with non-small cell lung cancer (NSCLC) was evaluated in a case-control study of 2707 individuals. The mechanism of the SNP’s biologic influence was explored with in vitro and in vivo experiments, including plasmid transfection, siRNA knockdown, flow cytometry assessment, and assays of cell proliferation, migration, invasion, and colony formation.ResultsAssociation analysis showed that A allele of SNP rs140618127 was associated with low risk of NSCLC in the Chinese population. Lab experiments indicated that SNP rs140618127 contained a binding site for miR-539-5p and the binding between miR-539-5p and LOC146880 resulted in declined phosphorylation of an oncogene, ENO1. The reduced phosphorylation of ENO1 led to decreased phosphorylation of PI3K and Akt, which is further linked to the decline in cell proliferation and tumor progression.ConclusionThe study demonstrates that SNP rs140618127 in lncRNA loc146880 provides an alternate binding site for microRNA miR-539-5p which affects the phosphorylation of ENO1 and activation of the PI3K and Akt pathway.

Serum levels of retinol-binding protein 4 and the risk of non-small cell lung cancer

Retinol binding protein 4 (RBP4), as an adipokine, has been identified to be associated with several types of cancer. However, no studies have assessed its effect on non-small cell lung cancer (NSCLC) risk. The objective of this study was to assess the association between serum RBP4 levels and the risk of NSCLC.A case-control study design was used to recruit 256 confirmed NSCLC cases and 256 age- and gender-matched healthy controls by frequency between August 2017 and January 2019. Serum RBP4 was measured using enzyme-linked immune absorbent assay before treatment. Unconditional logistic regression analysis was applied to estimate the odds ratio and 95% confidence interval (CI).Serum RBP4 level was significantly higher in NSCLC patients than those in the healthy control group (36.05 ± 8.28 vs 29.54 ± 7.71 μg/mL, P < .05). Higher serum RBP4 level was associated with increased risk of NSCLC (P trend = .001). Compare with those in the lowest tertile, the adjusted odds ratios were 1.85 (95% CIs 1.07–3.2) (P = .029) for the second tertile and 2.18 (95% CIs 1.37–3.45) (P = .001) for the highest tertile after adjusting for confounding variables. No interactions were observed after stratified analyses by body mass index and smoking status (P for interaction: .584 and .357).Our study indicated that serum RBP4 level was positively related to the risk of NSCLC. Additional studies with prospective design are required to confirm this finding.

Relevance of genetic polymorphisms in tobacco-related detoxifying enzymes in non-small cell lung carcinoma susceptibility

BackgroundTobacco smoking plays a role in the onset and development of non-small cell lung cancer (NSCLC). Biotransformation and detoxification of tobacco smoke carcinogens are brought about by xenobiotic-metabolizing enzymes (XME). Germline mutations in CYP1B1 (Ala119Ser) and GSTT1 (+/−) have been known to affect the functionality of these enzymes, thereby modifying their effect; amino acid substitution and complete gene deletion abolish enzyme activity. CYP1B1 (Ala119Ser) and GSTT1 (+/–) genotypic interactions and gene-smoking inteaction associated risk of NSCLC information is not documented in the literature. ObjectiveThe role of gene-gene and gene-smoking interaction with the clinicopathological parameters to estimate the risk of NSCLC among the North Indian population. MethodsCYP1B1 and GSTT1 genotypes were determined by the PCR-RFLP in 158 cases of NSCLC and 155 controls; demographical parameters and clinicopathological characteristics were recorded. ResultsGSTT1 (−/−) genotype demonstrated a four-fold risk of NSCLC and was significantly associated with squamous cell lung carcinoma (OR: 3.35). Synergistic interaction of CYP1B1 (Variant) and GSTT1 (−/−) enhanced the risk of NSCLC by 6.5 fold. CYP1B1 mutant genotypes in tobacco smokers showed a 3.5 fold risk, which was significantly (p = 0.02) higher than the non-smokers (OR: 1.67, p = 0.38). NSCLC risk with GSTT1 mutant genotype showed a similar trend of risk in both smokers (OR: 4.1) and non-smokers (OR: 3.8). ConclusionThe effect of CYP1B1 mutant appears to be a risk modifier in tobacco smokers, whereas deletions in GSTT1 (−/−) increases the risk of NSCLC in both smokers and non-smokers. A marked synergistic risk was evident when both mutations were present.

Association of phosphatase and tension homologue deleted on chromosome ten polymorphism rs1903858, but not serum levels with the risk of non-small-cell lung cancer: A case-control study.

BackgroundTo investigate the association between phosphatase and tension homologue deleted on chromosome ten (PTEN) gene polymorphisms and non–small‐cell lung cancer (NSCLC) and further identify whether these polymorphisms influence serum PTEN levels.MethodsA total of 152 NSCLC patients and 124 healthy controls were included in the study. PTEN gene rs11202586 (T > C) and rs1903858 (A > G) polymorphisms were detected using the multiple single‐base extension technique (SNaPshot). The serum PTEN levels were determined using an enzyme‐linked immunosorbent assay (ELISA) kit.ResultsThe rs1903858 AG, GG genotypes, and G allele were associated with a higher risk of NSCLC (odds ratio (OR) =2.079, 95% confidence interval (CI) = 1.087‐3.974, P = .027; OR = 1.897, 95%CI = 1.053‐3.419, P = .033; OR = 1.505, 95%CI = 1.065‐2.126, P = .020). Stratified analysis reveal that the rs1903858 GG genotype and G allele were associated with an increased risk of squamous cell carcinoma (SCC) (OR = 3.226, 95%CI = 1.075‐9.678, P = .037; OR = 1.873, 95%CI = 1.092‐3.212, P = .023). Among smokers, the rs1903858 G allele carriers have an increased risk of NSCLC (OR = 1.916, 95%CI = 1.023‐3.589, P = .042), but a decreased risk of NSCLC was found with the AT haplotype. With respect to the serum PTEN levels, no significant difference was noted between NSCLC patients and healthy controls in this study.ConclusionsThe study indicated that the rs1903858 gene polymorphism is associated with increased risk of NSCLC, particularly in SCC and smoker, and the haplotype AT was a protective factor for NSCLC. The serum PTEN levels were not associated with NSCLC.

Early Detection of Non-Small Cell Lung Cancer by Using a 12-microRNA Panel and a Nomogram for Assistant Diagnosis.

Background: We previously identified a 12-microRNA (miRNA) panel (miRNA-17, miRNA-146a, miRNA-200b, miRNA-182, miRNA-155, miRNA-221, miRNA-205, miRNA-126, miRNA-7, miRNA-21, miRNA-145, and miRNA-210) that aided in the early diagnosis of non-small cell lung cancer (NSCLC). We validated the diagnostic value of this miRNA panel and compared it with that of traditional tumor markers and radiological diagnosis. We constructed a nomogram based on the miRNA panel's results to predict the risk of NSCLC.Methods: Eighty-two participants with pulmonary nodules on a CT scan and who underwent a pathological examination and surgical treatment were enrolled in our study. Patients were randomly divided into a training group or a validation group. The miRNA concentrations were quantified by RT-PCR and log-transformed for analysis. The cutoff value was determined in the training group and then applied in the validation group. A comparison between the miRNAs and traditional tumor markers [CEA, NSE, and cytokeratin 19 fragment 21-1 (Cyfra21-1)] and radiological diagnosis was performed. A nomogram based on the miRNA panel's results to predict the risk of NSCLC was constructed.Results: The expression level of these 12 miRNAs was significantly higher in NSCLC patients than in benign patients. In the validation group, the specificity and positive predictive value were 96.4 and 95.8%, respectively, which were significantly higher than those using traditional tumor markers or radiological diagnosis. The sensitivity was 42.6%, which was also higher than that using tumor markers. Moreover, the sensitivity increased to 63.6% when the nodule diameters were larger than 2 cm. The miRNAs and seven clinical factors were integrated into the nomogram, and the calibration curves showed optimal agreement between the predicted and actual probabilities.Conclusions: Our miRNA panel has clinical value for the early detection of NSCLC. A nomogram was constructed and internally validated, and the results indicate that it can assist clinicians in making treatment recommendations in the clinic.

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.

Venous thromboembolism (VTE) incidence and risk factors in patients (pts) with non-small cell lung cancer (NSCLC) receiving front-line therapy.

e19293 Background: VTE incidence varies based on factors such as tumor type, stage, and treatment. There is limited data on VTE incidence and risk factors in NSCLC pts receiving first-line therapies, including immune checkpoint inhibitors (ICIs) and targeted therapies (TTs). Methods: This is a single institution retrospective cohort study of adult NSCLC pts who received first-line treatment between July 2003 and July 2019. Treatments included chemotherapy (chemo) (platinums, taxanes, pemetrexed, gemcitabine, etoposide, bevacizumab), ICI (pembrolizumab, nivolumab, atezolizumab, durvalumab), chemo + ICI, or TT (erlotinib, gefitinib, afatinib, osimertinib, crizotinib, alectinib, ceritinib). Diagnosis codes (ICD 9/10 codes) confirmed VTE (deep vein thrombosis and/or pulmonary embolism) and presence of risk factors which are summarized in Table. Landmark VTE incidence was estimated from cumulative incidence curves for time to VTE, death as a competing risk. Time to VTE distributions were compared between groups with Gray’s tests. Univariable and multivariable competing risk analyses identified risk factors for time to VTE. Results: In 1,618 evaluable pts, the median age was 66 years, 53% were male, 79% White, 18% Black, 58% had adenocarcinoma, 32% squamous cell carcinoma, and 47% metastatic disease. 1178 received chemo, 172 ICIs, 157 chemo + ICI, and 111 TTs. 6-month VTE rates per arm were 5.3%, 7.0%, 7.2%, and 12.0% and 12-month rates were 8.9%, 8.1%, 11.7%, and 13.3%, respectively. Cumulative incidence of VTE was not significantly different between treatment groups (p = .27). Univariable and multivariable analyses are summarized in the Table below. Conclusions: Treatment type was not associated with VTE risk in first-line NSCLC, but rates were numerically highest in pts receiving TTs. Khorana risk score was significantly associated with VTE risk and may identify those likely to benefit from thromboprophylaxis. [Table: see text]

Characterising the impact of pneumonia on outcome in non-small cell lung cancer: identifying preventative strategies.

BackgroundInfections remain a part of the natural course of cancer, and lung cancer patients often present with some form of respiratory infection that can lead to their ultimate demise.MethodsData was gathered concerning all unplanned hospital admissions (UHAs) to our centre from three separate patient cohorts; non-small cell lung cancer (NSCLC) patients (cohort 1), “other cancer” patients (breast, prostate, colon) (cohort 2) and all non-cancer patients (cohort 3).ResultsAcross the three cohorts, there were 455, 1,190 and 54,158 individual patient UHAs to our centre respectively. Within the NSCLC cohort, 164 UHAs were as a direct result of pneumonia (36.0%), compared to 1.3% and 2.2% in the other two cohorts (P<0.0001). In-hospital mortality and length of hospital stay were significantly higher in the pneumonia sub-group of NSCLC patients only compared with the other two patient cohorts (P<0.0001 and P=0.011 respectively). Within the NSCLC cohort, Patient age, pneumococcal vaccination status, pneumonia admission, smoking status and specific tumour stages were identified as significant independent risk factors for in-hospital mortality. Odds ratios of 0.160 for positive vaccination status and 9.522 for pneumonia admission indicate that for NSCLC patients admitted to hospital with a pneumonia without previous pneumococcal vaccination in the last 5 years, the odds of death were almost 60-fold higher.ConclusionsVigilance for infection, early diagnosis with adequate assessment and efforts to identify a culprit organism should be a priority when faced with these patients. Infection prevention strategies should be further explored to address this high mortality risk in NSCLC.