Lung Cancer In Chinese Population Research Articles

Effectiveness Evaluation of Low-dose Spiral Computed Tomography for Lung Cancer Screening in Minhang District of Shanghai

Low-dose spiral computed tomography (LDCT) has been recommended for lung cancer screening in high-risk populations. However, evidence from Chinese populations was limited due to the different criteria for high-risk populations and the short-term follow-up period. This study aimed to evaluate the effectiveness in Chinese adults based on the Lung Cancer Screening Program in Minhang District of Shanghai initiated in 2013. A total of 26,124 subjects aged 40 years or above were enrolled in the Lung Cancer Screening Program during the period of 2013 and 2017. Results of LDCT examination, and screen-detected cancer cases in all participants were obtained from the Reporting System of the Lung Cancer Screening Program. The newly-diagnosed cases and their vital status up to December 31, 2020 were identified through a record linkage with the Shanghai Cancer Registry and the Shanghai Vital Statistics. Standardized incidence ratio (SIR) and 95%CI were calculated using the local population at ages of 40 or above as the reference. Proportions of early-stage cancer (stage 0-I), pathological types, and 5-year observed survival rates of lung cancer cases were estimated and compared between the cases derived from the screened and non-screened populations. Cox regression models were applied to evaluate the hazard ratio (HR) and 95%CI of LDCT screening with all-cause death of the lung cancer cases. The crude and age-standardized incidence of lung cancer in screened population were 373.3 (95%CI: 343.1-406.1) and 70.3 per 100,000 person-years, respectively, with an SIR of 1.8 (95%CI: 1.6-1.9), which was observed to decrease with following-up time. The early-stage cancer accounted for 49.4% of all lung cancer cases derived from the screened population, significantly higher than 38.4% in cases from the non-screened population during the same period (P<0.05). The proportion of lung adenocarcinoma (40.7% vs 35.9%) and 5-year survival rate (53.7% vs 41.5%) were also significantly higher in the cases from the screened population (all P<0.05). LDCT screening was associated with 30% (HR=0.7, 95%CI: 0.6-0.8) reduced all-cause deaths of the cases. The participants of the screening program are at high-risk of lung cancer. LDCT favors the early-detection of lung cancer and improves 5-year survival of the screened cases, indicating a great potential of LDCT in reducing the disease burden of lung cancer in Chinese populations.

Low-dose CT for lung cancer early-detection in China: Findings from a screening program in Shanghai

Abstract Background Low-dose computed tomography (LDCT) has been recommended for lung cancer screening in high-risk populations. This study is aimed to evaluate the effects of LDCT screening for lung cancer in Chinese populations. Methods A total of 26124 subjects aged over 40 years were enrolled from the Minhang District of Shanghai, China, 2013-2017. The detection of lung cancer and the survival status of cases up to Dec 31,2018 were obtained. Standardized incidence ratio (SIR) was calculated for the screened populations relative to the local general population. Three-year survival rates and proportion of early-stage (stage 0-I) cancer were estimated for all cases from general population and for screen-detected cases. For 12184 high-risk individuals in the screened population, a total of 12184 matched controls without LDCT were identified using propensity score matching (PSM), lung cancer mortality and all-cause mortality were calculated and compared between groups. Results The crude incidence of lung cancer in the screened population was 426.6 (95%CI: 387.4-470.2) per 100000 person-years, with an overall SIR of 2.3 (95%CI: 2.0-2.5). The SIR decreased with the highest level in the first year [3.8 (95%CI: 3.3-4.3)], and a lower level over 3 years [0.6 (95%:CI: 0.5-0.7)]. Early-stage lung cancer accounted for 26.3% of screen-detected cases, significantly higher than 15.3% in all cases during the same period. The 3-year survival rate was also higher in screen-detected cases (60.4%) than all cases (50.9%). Compared with the matched control group, the screened group had a 32.0% (95%CI: 0.47- 0.99) reduced lung cancer mortality and a 56% (95%CI: 0.37-0.52) decreased all-cause mortality. The proportion of early-stage lung cancer was also higher in cases screened-detected than in non-screened (28.9% vs 11.8%, p &amp;lt; 0.05). Conclusions Our results prove the benefits of LDCT screening and its great potential in reducing the disease burden of lung cancer in Chinese populations. Key messages • LDCT screening improved the detection of lung cancer in Chinese populations, and increased the proportion of early-stage cancer and 3-year survival rate of detected lung cancer cases. • LDCT screening decreased 32% of lung cancer mortality and 56% of all-cause mortality in Chinese populations.

Meta-analysis of lung cancer in Chinese population in genetic predisposition

The prevention and diagnosis of lung cancer in the Chinese population has received extensive attention in past few years. Many studies have suggested that genetic predisposition may be a risk factor for lung cancer and an important means for early diagnosis of carcinoma of the lung. At present, the research on the molecular mechanism of lung cancer has been carried out on the whole genome, and a large number of SNPs have also been found in the Chinese population, these results suggest that the genetic predisposing factors of lung cancer in Chinese population are different from those in foreign population.

Variants in CYP2J2 and CYP2C9 Contribute to Susceptibility of Lung Cancer.

Cytochrome P450 (CYP) enzymes are involved in the metabolism of xenobiotic and carcinogen. In the study, we evaluated the association of CYP2J2 and CYP2C9 variants with lung cancer. Five polymorphisms in CYP2J2 and four polymorphisms in CYP2C9 were genotyped in 507 lung cancer patients and 505 controls with Agena MassARRAY platform. The linkage of variants with lung cancer risk was evaluated by odds ratio (OR) and 95% confidence interval (CI) in genetic models and haplotype analyses. We found that CYP2C9 rs1934967 alleles were associated with lung cancer risk (P < 0.05). In stratified analysis, rs2280274 (women, non-smoker, non-drinker and lymphatic metastasis), rs11207535 (non-smoker and non-drinker), rs10889159 (non-smoker and non-drinker) of CYP2J2, whereas rs1934967 (age ≤ 60m, BMI > 24, squamous carcinoma) of CYP2C9 decreased lung cancer risk (P < 0.05). In addition, the results of linkage disequilibrium (LD) analysis showed that rs2280274|rs4388726 - TG (with adjustment: P = 0.042) of CYP2J2 and rs10509679|rs1934967|rs1934968|rs9332220 - GTGG (without adjustment: P = 0.044) of CYP2C9 were linked with a significantly decreased lung cancer risk. Our results indicated genetic variants in CYP2J2 and CYP2C9 might contribute to the susceptibility of lung cancer in Chinese population.

MicroRNA in the diagnosis of lung cancer: An overview of ten systematic reviews.

To provide theoretical support for clinical diagnosis of lung cancer through an overview of systematic reviews (SRs) of the diagnostic value of miRNA. We searched PubMed, Embase, and the Cochrane Library to collect SRs of the diagnostic value of microRNA for lung cancer until April 2021. A comprehensive database search was carried out, screened, and extracted information independently by two researchers, to compare and analyze the sensitivity and specificity of relevant literatures. The ROBIS tool was applied to assess the risk of bias of included SRs and meta-analysis. A total of 10 SRs were included the results of risk of bias assessment by ROBIS tool showed: 10 SRs completely matched the four questions of phase one. In phase two, nine SRs were low risk of bias in the including criteria field; one study was uncertain; nine SRs were low risk of bias, one study was uncertain in the literature search and screening field; nine SRs were low risk of bias in the data abstraction and quality assessment field, one SR was high; and 10 SRs were low risk of bias in the data synthesis field. In the phase three of comprehensive risk of bias results, 8 studies were low risk, one was high risk, and one study was uncertain. MiRNA had a pooled sensitivity of 0.77 (95% CI: 0.73-0.81) and specificity of 0.81 (95% CI: 0.79-0.84). The summarized area under the SROC curve was 0.86 (95% CI: 0.83-0.89), and combined diagnostic odds ratio was 14.68 (10.87-19.81). The sensitivity and specificity of multiple MicroRNA was 0.80 (0.73-0.85) and 0.80 (0.76-0.83); the sensitivity and specificity of single MicroRNA was 0.74 (0.69-0.79) and 0.83 (0.80-0.88). MiRNA is a promising biomarker for the diagnosis of lung cancer in Chinese population, with advanced sensitivity and specificity. It provides a faster and less invasive assessment of lung cancer than other markers that require histopathological analysis. We should improve the reliability of the conclusion. The construction of diagnosis for lung cancer provides reliable evidence support.

Diagnostic value of tumor associated autoantibody panel in early detection of lung cancer in Chinese population: Protocol for a prospective, observational, and multicenter clinical trial

Lung cancer is the leading cause of cancer deaths. Although targeted therapies and programmed cell death protein 1 (PD-1) blockade have offered great advances, five-year survival rates remained low. Diagnosis of lung cancer at an earlier stage is the most efficient approach to improve survival. Tumor associated autoantibodies (TAAb) have been proven a promising innovative biomarker of lung cancer. We aimed to comprehensively evaluate the sensitivity, specificity, and accuracy of TAAbs in lung cancer detection, especially in early-stage patients, through a multicenter prospective observational clinical trial, and to screen out the novel combination of TAAbs with the best detection value for Chinese population. We aimed to enroll 1,400 participants from three clinical centers and divide into two cohorts. One cohort is participants with newly pathologically confirmed lung cancer as the case cohort, and the other is participants with benign nodules, matched healthy controls and other benign lung diseases as the control cohort. Cases and controls were randomly distributed into training or validation set. The level of 14 autoantibody candidates in their plasma were detected. A Monte-Carlo Simulated Annealing method was implemented to develop a composite panel of autoantibodies to distinguish between matched lung cancer cases and controls in the training set. The newly developed autoantibody panel was tested in the validation set for sensitivity, specificity and accuracy. This is the first and largest clinical trial designed to develop a novel autoantibody panel for lung cancer detection specifically for Chinese people. We performed a multicenter, prospective, observational study to find a novel panel of autoantibody markers that can help the diagnosis of lung cancer and the characterization of pulmonary nodules in Chinese population. The results may help to provide evidence-based recommendations to clinicians for lung cancer early detection and pulmonary nodule management. This study is registered in the ClinicalTrials.gov (NCT04216511).

Cost-effectiveness of lung cancer screening combined with nurse-led smoking cessation intervention: A population-based microsimulation study

BackgroundThe appropriate screening inclusion criteria of low-dose computed tomography screening for lung cancer in Chinese population remains unclear and the effect of combining screening with nurse-led smoking cessation intervention is poorly understood as well. ObjectiveWe compared the benefits and costs of lung cancer screening with and without nurse-led smoking cessation intervention in different inclusion criteria to help select optimal screening strategies. MethodsDifferent screening strategies were set based on diverse starting ages, smoking pack-year and whether nurse-led smoking cessation intervention was applied. We use nationally representative data published by the China Health and Retirement Longitudinal Survey, based on a microsimulation model, to predict incremental cost-effectiveness ratio and net health benefits under different strategies. ResultsThe incremental cost-effectiveness ratios for all lung cancer screening strategies were less than three times GDP per capita, and screening combined with smoking cessation intervention had lower incremental cost-effectiveness ratios. The largest net health benefits and probability of cost-effectiveness were both obtained in the strategy which conducted screening and nurse-led smoking cessation intervention for people over 45 years with at least 20 pack-year smoking history. In strategies screening alone, it was obtained in screening for people over 50 years and with at 20 pack-year smoking history. ConclusionsNurse-led smoking cessation intervention is recommended provided in conjunction with lung cancer screening. The optimal strategy is conducted screening with cessation intervention for current smokers or smoking quitters in the past 15 years who are over 45 years with at least 20 pack-year smoking history. For strategies screening alone, the target population should be over 50 years old with at least 20 pack year smoking history, when willingness to pay less than three times GPD per capita.

TLR4 regulatory region variants reduce the susceptibility of small-cell lung cancer in Chinese population.

Toll-like receptors (TLRs) participate in the induction and regulation of immune responses and are closely related to the occurrence and development of small-cell lung cancer (SCLC). This study aimed to investigate the impact of polymorphisms in the regulatory regions of TLRs on the susceptibility of SCLC. The case-control study included 304 SCLC patients and 304 healthy controls. TLRs gene polymorphisms were genotyped by PCR-restrictive fragment length polymorphism analysis and TaqMan assay. Unconditional logistic regression was used to estimate odds ratio (OR) and its 95% confidence interval (95% CI). Our results showed that TLR4 rs1927914 GG genotype and TLR4 rs7869402 TT genotype reduced the risk of SCLC with OR (95% CI) of 0.54 (0.32-0.90) and 0.47 (0.28-0.80), respectively. Stratified analysis suggested that TLR4 rs1927914 GG genotypes significantly reduced the risk of SCLC among male (OR = 0.35; 95% CI, 0.18-0.69; P < 0.01), the younger patients (OR = 0.49; 95% CI, 0.26-0.94; P = 0.03) and non-drinkers (OR = 0.47; 95% CI, 0.24-0.89; P = 0.02). TLR4 rs7869402 CT or TT genotype significantly reduced the susceptibility to SCLC among male patients (OR = 0.37; 95% CI, 0.19-0.71, P < 0.01), the younger patients (OR = 0.41; 95% CI, 0.22-0.79; P < 0.01), smokers (OR = 0.25; 95% CI, 0.10-0.60; P < 0.01) and drinkers (OR = 0.31; 95% CI, 0.11-0.88; P = 0.03). TLR3 rs5743303, TLR4 rs11536891, TLR5 rs1640816 and TLR7 rs3853839 had no significant correlation with the risk of SCLC. These findings emphasized the important role of TLR4 in the development of SCLC.

Associations of systemic inflammation markers with identification of pulmonary nodule and incident lung cancer in Chinese population.

ObjectivesNeutrophil‐to‐lymphocyte ratio (NLR), platelet‐to‐lymphocyte ratio (PLR), and systemic immune‐inflammation index (SII), easily accessible systemic inflammation response parameters, were reported to associate with poor lung cancer prognosis. However, research on the effects of these markers on the risk of positive nodules (PNs) and lung cancer is limited.MethodsParticipants in this retrospective study were those who had their first computed tomography (CT) screening at Jiangsu Province Hospital's Health Promotion Center between January 1, 2017 and December 31, 2020. We identified PNs (≥6 mm in diameter) from free text of CT reports and lung cancer from medical records. Multivariate logistic analysis was used to assess the association between NLR, PLR, or SII and PNs or lung cancer.ResultsThe detected rate of PNs was 9.60% among the 96,476 participants. Age, smoking and body mass index were possible influencing factors for PNs. We observed linear dose‐effect relationship between NLR, PLR, or SII and PNs (p non‐linear > 0.05). Compared with low quintile, participants with top quintiles of NLR, PLR or SII had an increased risk of PNs, with the adjusted ORs of 1.19 (1.11–1.28), 1.11 (1.04–1.19) or 1.11 (1.03–1.18), respectively. Meanwhile, NLR showed the U‐shaped relationship with lung cancer, with adjusted ORs of 1.40 (1.08–1.81) comparing highest NLR quintile to the third quintile. The high PLR and SII showed significantly associated with lung cancer with adjusted ORs of 1.29 (0.99–1.68) and 1.35 (1.04–1.74) comparing to the lowest quintile.ConclusionsThe high levels of systemic inflammation markers were associated with the risk of positive pulmonary nodules and lung cancer, which suggested systemic immune response may be an important pre‐clinical feature for the early identification of diseases.

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.

Genome-wide gene-smoking interaction study identified novel susceptibility loci for non-small cell lung cancer in Chinese populations.

Gene-smoking interactions play important roles in the development of non-small cell lung cancer (NSCLC). To identify single-nucleotide polymorphisms (SNPs) that modify the association of smoking behavior with NSCLC risk, we conducted a genome-wide gene-smoking interaction study in Chinese populations. The genome-wide interaction analysis between SNPs and smoking status (ever- versus never-smokers) was carried out using genome-wide association studies of NSCLC, which included 13 327 cases and 13 328 controls. Stratified analysis by histological subtypes was also conducted. We used a genome-wide significance threshold of 5 × 10-8 for identifying significant gene-smoking interactions and 1 × 10-6 for identifying suggestive results. Functional annotation was performed to identify potential functional SNPs and target genes. We identified three novel loci with significant or suggestive gene-smoking interaction. For NSCLC, the interaction between rs2746087 (20q11.23) and smoking status reached genome-wide significance threshold [odds ratio (OR) = 0.63, 95% confidence interval (CI): 0.54-0.74, P = 3.31 × 10-8], and the interaction between rs11912498 (22q12.1) and smoking status reached suggestive significance threshold (OR = 0.72, 95% CI: 0.63-0.82, P = 8.10 × 10-7). Stratified analysis by histological subtypes identified suggestive interactions between rs459724 (5q11.2) and smoking status (OR = 0.61, 95% CI: 0.51-0.73, P = 7.55 × 10-8) in the risk of lung squamous cell carcinoma. Functional annotation indicated that both classic and novel biological processes, including nicotine addiction and airway clearance, may modulate the susceptibility to NSCLC. These novel loci provide new insights into the biological mechanisms underlying NSCLC risk. Independent replication in large-scale studies is needed and experimental studies are warranted to functionally validate these associations.

A cross-tissue transcriptome-wide association study identifies novel susceptibility genes for lung cancer in Chinese populations.

Although dozens of susceptibility loci have been identified for lung cancer in genome-wide association studies (GWASs), the susceptibility genes and underlying mechanisms remain unclear. In this study, we conducted a cross-tissue transcriptome-wide association study (TWAS) with UTMOST based on summary statistics from 13 327 lung cancer cases and 13 328 controls and the genetic-expression matrix over 44 human tissues in the Genotype-Tissue Expression (GTEx) project. After further evaluating the associations in each tissue, we revealed 6 susceptibility genes in known loci and identified 12 novel ones. Among those, five novel genes, including DCAF16 (Pcross-tissue = 2.57 × 10-5, PLung = 2.89 × 10-5), CBL (Pcross-tissue = 5.08 × 10-7, PLung = 1.82 × 10-4), ATR (Pcross-tissue = 1.45 × 10-5, PLung = 9.68 × 10-5), GYPE (Pcross-tissue = 1.45 × 10-5, PLung = 2.17 × 10-3) and PARD3 (Pcross-tissue = 5.79 × 10-6, PLung = 4.05 × 10-3), were significantly associated with the risk of lung cancer in both cross-tissue and lung tissue models. Further colocalization analysis indicated that rs7667864 (C > A) and rs2298650 (G > T) drove the GWAS association signals at 4p15.31-32 (OR = 1.09, 95%CI: 1.04-1.12, PGWAS = 5.54 × 10-5) and 11q23.3 (OR = 1.08, 95%CI: 1.04-1.13, PGWAS = 5.55 × 10-5), as well as the expression of DCAF16 (βGTEx = 0.24, PGTEx = 9.81 × 10-15; βNJLCC = 0.29, PNJLCC = 3.84 × 10-8) and CBL (βGTEx = -0.17, PGTEx = 2.82 × 10-8; βNJLCC = -0.32, PNJLCC = 2.61 × 10-7) in lung tissue. Functional annotations and phenotype assays supported the carcinogenic effect of these novel susceptibility genes in lung carcinogenesis.

Diagnostic value of microRNA-25 in patients with non-small cell lung cancer in Chinese population: A systematic review and meta-analysis.

Previous studies have shown that microRNA-25 (miR-25) plays a key role in the occurrence and development of non-small cell lung cancer (NSCLC). Many studies have shown that there is a significant increment of miR-25 in circulating blood of patients with NSCLC. The meta-analysis aims to explore diagnostic value of miR-25 in NSCLC in Chinese population. PubMed, Web of science, Excerpta Medica Database, China national knowledge infrastructure and China Wanfang database were searched to collect studies upon correlation between miR-25 and diagnosis of the patients with NSCLC until April 2020. Combined sensitivity, specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio and area under receiver operating characteristic curve were calculated by Stata 15.0 software. Literature assessment was conducted according to quality assessment of diagnostic accuracy studies, and documents with scores above or equal to 11 were included in this meta-analysis. Six studies were included, including 480 cases with NSCLC and 451 healthy controls. The combined sensitivity (0.75, 95% confidence interval [CI]: 0.69∼0.80), specificity (0.81, 95% CI: 0.76∼0.86), positive likelihood ratio (4.04, 95% CI: 3.14∼5.20), negative likelihood ratio (0.31, 95% CI: 0.25∼0.37), diagnostic odds ratio (13.09, 95% CI: 9.37∼18.29) and area under curve (0.85, 95% CI: 0.82∼0.88) indicated that miR-25 had desirable diagnostic accuracy for NSCLC. MiR-25 can be applied in diagnosis of NSCLC and has potential of becoming a biomarker for detection of patients with early NSCLC in Chinese population.

Genetic Polymorphisms of PRNCR1 and Lung Cancer Risk in Chinese Northeast Population: A Case-Control Study and Meta-Analysis.

Long noncoding RNAs (lncRNAs) play vital roles in development and progression of various cancers. To investigate the relationship between three tag single-nucleotide polymorphisms (SNPs) (rs13252298, rs1016343, and rs1456315) in lncRNA prostate cancer-associated noncoding RNA 1 (PRNCR1) and lung cancer (LC) risk, we conducted this study. First, we performed a case-control study, including 576 LC patients and 612 cancer-free controls. Second, a meta-analysis was used to evaluate the association of selected SNPs with risk of overall cancer. We found that rs13252298 and rs1456315 were strongly correlated with risk of LC, nonsmall cell lung cancer (NSCLC), and lung adenocarcinoma. For rs13252298, individuals carrying GG genotype had increased risks of LC compared with those carrying AA genotype (adjusted odds ratio [OR] = 1.565, 95% CI = 1.091-2.245, p = 0.015). A significant result was also found in recessive model with adjusted OR of 1.719. Individuals with GG genotype of rs1456315 were at increased risks of LC compared with those carrying AA genotype. Similar results were found in NSCLC patients. Meta-analysis showed that rs1016343 and rs13252298 were associated with overall cancer. But for rs1016343, no significant association was observed in Asians. In conclusion, rs13252298 and rs1456315 in PRNCR1 may be genetic susceptibility factors for LC in Chinese population. These results need to be confirmed by further studies.

Screening of significant oncogenic changes in air pollution-related lung cancer in Chinese population.

BackgroundAir pollution-related lung cancer has been considered as a deteriorating public health problem worldwide, particularly in developing countries. The highly air polluted regions in China particularly Xuanwei and Fuyuan counties have markedly high lung cancer rates and are considered as good models to study air pollution-related lung cancer. The present study investigated the clinically significant oncogenes in air pollution-related lung cancers.MethodsA combination of reverse transcriptase PCR (RT-PCR) and DNA sequencing was applied to examine the expression, mutations, or fusions of target genes, including human epidermal growth factor receptor 2 (HER2), echinoderm microtubule-associated protein-like 4-anaplastic lymphoma kinase (EML4-ALK), and cluster of differentiation 74-ROS proto-oncogene 1 (CD74-ROS1).ResultsOf the 82 patients with lung cancer, 20.7% (17/82) exhibited HER2 up-regulation, and 1.2% (1/82) harbored HER2 insertion at exon 20. HER2 overexpression was not associated with air pollution levels and smoking status. A total of 6.1% (5/82) samples exhibited ALK gene rearrangements; two belonged to EML4-E2 + ALK-E20 and three were EML4-E13 + ALK-E20; all the five cases occurred either in smokers or in patients from the most air-polluted region. A total of 3.6% (3/82) carried the CD74-ROS1 fusion gene (CD74-E6 + ROS1-E34); the fusion event was not statistically associated with air pollution levels.ConclusionsThe high rates of prevalence indicated in the present study suggest that the screening of HER2 overexpression and EML4-ALK fusion events may assist in guiding treatment in air pollution-related lung cancer; the RT-PCR-based test proposed in this study may be a useful tool in clinical applications to screen these genetic changes.

Correlation of gene polymorphisms of vascular endothelial growth factor with grade and prognosis of lung cancer

BackgroundVascular endothelial growth factor (VEGF) gene is highly polymorphic, and single nucleotide polymorphisms (SNP) of VEGF gene are associate with cancer prognosis. This study aimed to analyze the correlation of VEGF gene polymorphisms with grade and prognosis of lung cancer.MethodsA total of 458 Chinese patients with primary lung cancer were enrolled from September 2008 to October 2013. The genotypes of −2578C > A, −1154G > A, − 460 T > C, and + 405G > C were analyzed in white blood cells from patients using polymerase chain reaction based restriction fragment length polymorphism.ResultsOur data showed that –1154G > A polymorphism was significantly associated with tumor stages, but all four tested VEGF gene polymorphisms had no significant effect on survival.ConclusionsVEGF polymorphisms may relate to stage of lung cancer in Chinese population.

TERT-rs33963617 and CLPTM1L-rs77518573 reduce the risk of non-small cell lung cancer in Chinese population

BackgroundGenome-wide association studies (GWAS) have identified 5p15.33 as a susceptible locus for lung cancer. However, for non-small cell lung cancer (NSCLC), low-frequency risk variants in this region have not been systematically studied. We intended to explore the associations between low-frequency variants on 5p15.33 and NSCLC using a next-generation sequencing based approach in this study. MethodsWe have acquisited the variation spectrum of 400 NSCLC patients on 5p15.33 by sequencing the targeted region before. Candidate variants were primarily selected by restricting the minor allele frequency (MAF 1–5%) and then by comparing their frequency in 400 NSCLC patients with 1008 East Asians from The genome Aggregation Database (gnomAD). The associations between candidate variants and NSCLC were discovered and replicated in two case-control sets: discovery stage with 960 cases and 916 controls, and replication stage with 1596 cases and 1614 controls in total. ResultsFive low-frequency variants were selected as our candidates and subsequent association analyses showed that 2 polymorphisms were significantly associated with risk of NSCLC, including rs33963617 (OR = 0.63, 95% CI: 0.53–0.76, P = 3.80 × 10−7) in TERT and rs77518573 (OR = 0.73, 95% CI: 0.63–0.84, P = 2.00 × 10−5) in upstream of CLPTM1L. When stratified by histologic subtype, a significant association was only investigated in adenocarcinoma for rs77518573. We also observed an obvious cumulative effect of the two significant variants. ConclusionsWe newly identified two NSCLC related variants on chromosome 5p15.33. Both TERT-rs33963617 and CLPTM1L-rs77518573 conferred reduced risk for NSCLC in Chinese Han population.

Genetic variations in miR-125 family and the survival of non-small cell lung cancer in Chinese population.

To investigate the associations between the functional single nucleotide polymorphisms (SNPs) in the miR‐125 family and the survival of non‐small cell lung cancer (NSCLC) patients, we systematically selected six functional SNPs located in three pre‐miRNAs (miR‐125a, miR‐125b‐1, miR‐125b‐2). Cox proportional hazard regression analyses were conducted to estimate the crude and adjusted hazard ratios (HRs) and their 95% confidence intervals (CIs). Reporter gene luciferase assay was performed to examine the relationship between the SNPs and transcriptive activity of the miRNAs. The expression of miRNAs in different cells was detected using quantitative real‐time PCR assay. We found that rs2241490 (upstream of miR‐125b‐1, G > A, adjusted HR = 1.24, 95%CI = 1.05‐1.48, P = 0.014, in dominant model; adjusted HR = 1.18, 95%CI = 1.03‐1.35, P = 0.014, in additive model), rs512932 (upstream of miR‐125b‐1, A > G, dominant model: adjusted HR = 1.25, 95%CI = 1.05‐1.48, P = 0.013) and rs8111742 (upstream of miR‐125a, G > A, dominant model: adjusted HR = 0.84, 95%CI = 0.71‐1.00, P = 0.047) were associated with the prognosis of 1001 Chinese NSCLC patients. The combined analysis of the three SNPs related the number of risk alleles (rs2241490‐A, rs512932‐G and rs8111742‐G) to death risk of NSCLC in a locus‐dosage mode (P for trend <0.001). Furthermore, luciferase reporter gene assay showed significantly higher levels of luciferase activity with rs512932 variant G than that with A allele in 293T, SPC‐A1 and A549 cell lines. Besides, miR‐125b was highly expressed in lung cancer cells than the normal lung cell. Our study indicated that genetic variations in miR‐125 family were implicated in the survival of NSCLC patients. Larger population‐based and functional studies are needed to verify these findings.

Functional polymorphisms on chromosome 5p15.33 disturb telomere biology and confer the risk of non-small cell lung cancer in Chinese population.

The chromosome 5p15.33 has been reported as a susceptibility locus for lung cancer. However, causal variants in this region have not been fully uncovered. In this study, we intended to identify functional polymorphisms associated with non-small cell lung cancer (NSCLC) susceptibility in Chinese population. A targeted sequencing on 5p15.33 region was conducted in 400 NSCLC cases. We selected candidate variants by comparing genotypic frequency with data from 1000 Genomes Project, and their associations with NSCLC were validated in 985 cases and 970 controls. The relationships between risk variants and telomere length were evaluated in 774 healthy subjects. Luciferase assays and electrophoretic mobility shift assays (EMSA) were performed to explore potential functions and reveal carcinogenic mechanisms. As a result, we identified 1478 variants through targeted sequencing and selected 17 candidates. Four polymorphisms exhibited prominent associations with lung cancer risk, including rs7726159 (OR = 1.34, 95%CI: 1.18-1.52, P = 7.78 × 10-6 ), rs10054203 (OR = 1.29, 95%CI: 1.13-1.46, P = 1.37 × 10-4 ), rs2736107 (OR = 1.28, 95%CI: 1.11-1.47, P = 5.14 × 10-4 ), and rs2853677 (OR = 1.23, 95%CI: 1.08-1.39, P = 0.002). The minor allele of rs7726159 and rs10053203 were associated with long telomeres (P = 0.008 and 0.036, respectively). Mechanistically, the rs7726159-A increased TERT transcription through mediating allele-specific MYC binding. In conclusion, the functional variant rs7726159 confers lung cancer susceptibility might by affecting MYC binding and inducing telomere lengthening, which provides a new insight into the crucial role of telomere biology in tumorigenesis.

Single nucleotide polymorphism in the 3\u2032 untranslated region of LPP is a risk factor for lung cancer: a case-control study

BackgroundSingle nucleotide polymorphisms (SNPs) in 3′-untranslated region (UTR) of genes related with cell-matrix adhesions and migration might affect miRNA binding and potentially affect the risk of cancer. The present study aimed to screen SNPs in 3′ UTR of cancer-related genes and investigate their contribution to the susceptibility of lung cancer.MethodsSeven SNPs were selected and genotyped in a case-control study (322 lung cancer patients and 384 controls) among Chinese Han population. Odds ratio (OR) and 95% confidence intervals (CIs) were calculated by logistic regression adjusted for age and gender in multiple genetic models.ResultsIn stratified analyses by gender, three (rs1064607, rs3796283 and rs2378456) of LPP gene were associated with a significantly increased susceptibility for lung cancer among male population. Besides, LPP rs2378456 weakened lung cancer risk in female. LPP rs1064607 polymorphism was significantly correlated with increased risk of lung adenocarcinoma. Furthermore, AA genotype of TNS3 rs9876 polymorphism was associated with lymphatic metastasis.ConclusionOur results provides evidence for the impact of LPP polymorphisms on the susceptibility to lung cancer in Chinese population.