Non-small Cell Lung Cancer In Chinese Population Research Articles

Changes in serum amino acid levels in non-small cell lung cancer: a case-control study in Chinese population.

BackgroundPrevious studies have shown the alteration of amino acid (AA) profile in patients with non-small cell lung cancer (NSCLC). However, there is little data regarding AA profile in NSCLC in Chinese population. The aim of this study was to evaluate AA profile in Chinese NSCLC patients, explore its utility in sample classification and further discuss its related metabolic pathways.MethodsThe concentrations of 22 AAs in serum samples from 200 patients with NSCLC and 202 healthy controls were determined by liquid chromatography-tandem mass spectrometer (LC-MS/MS). AA levels in different tumor stages and histological types were also discussed. The performance of AA panel in classifying the cases and controls was evaluated in the training data set and validation data set based on the receiver operating characteristic (ROC) curve, and the important metabolic pathways were identified.ResultsThe concentrations of tryptophan (Trp), phenylalanine (Phe), isoleucine (Ile), glycine (Gly), serine (Ser), aspartic acid (Asp), asparagine (Asn), cystein (Cys), glutamic acid (Glu), ornithine (Orn) and citrulline (Cit) were significantly altered in NSCLC patients compared with controls (all P-FDR < 0.05). Among these, four AAs including Asp, Cys, Glu and Orn were substantially up-regulated in NSCLC patients (FC ≥ 1.2). AA levels were significantly altered in patients with late-stage NSCLC, but not in those with early-stage when comparing with healthy controls. In terms of histological type, these AAs were altered in both adenocarcinoma and squamous cell carcinoma. For discrimination of NSCLC from controls, the area under the ROC curve (AUC) was 0.80 (95% CI [0.74–0.85]) in the training data set and 0.79 (95%CI [0.71–0.87]) in the validation data set. The AUCs for early-stage and late-stage NSCLC were 0.75 (95% CI [0.68–0.81]) and 0.86 (95% CI [0.82–0.91]), respectively. Moreover, the model showed a better performance in the classification of squamous cell carcinoma (AUC = 0.90, 95% CI [0.85–0.95]) than adenocarcinoma (AUC = 0.77, 95% CI [0.71–0.82]) from controls. Three important metabolic pathways were involved in the alteration of AA profile, including Gly, Ser and Thr metabolism; Ala, Asp and Glu metabolism; and Arg biosynthesis.ConclusionsThe levels of several AAs in serum were altered in Chinese NSCLC patients. These altered AAs may be utilized to classify the cases from the controls. Gly, Ser and Thr metabolism; Ala, Asp and Glu metabolism and Arg biosynthesis pathways may play roles in metabolism of the NSCLC patient.

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.

Dyslipidemia and non-small cell lung cancer risk in Chinese population: a case-control study

BackgroundNumerous studies reported that dyslipidemia was associated with cancer risk. However, few studies investigated the associations between dyslipidemia and non-small cell lung cancer (NSCLC).MethodsFour hundred twenty-four histologically confirmed NSCLC cases and 414 controls, matched for age and sex, were enrolled to examine the relationship between dyslipidemia and NSCLC. Demographic and clinical data were obtained from patients’ medical records and telephone interviews. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression.ResultsAbnormal triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels showed statistically significant coexistence with NSCLC compared with controls. Higher levels of TG were associated with a higher risk of NSCLC (OR = 1.541, 95% CI, (1.072–2.215)). The odds ratios (ORs) for NSCLC for normal and high levels of HDL-C versus those with a low level of HDL-C were 0.337(95% CI, (0.242–0.468)) and 0.288(95% CI, (0.185–0.448)), respectively. After adjustment for age, sex, smoking status, hypertension, body mass index, diabetes and lipid profiles, the adjusted OR for normal and high levels of HDL-C were 0.320(95% CI, (0.218–0.470)) and 0.233(95% CI, (0.134–0.407)), respectively. However, after adjustment, high levels of TG increased the risk of NSCLC but not significantly (OR = 1.052, 95% CI (0.671–1.649)).ConclusionsThis study provided evidence that dyslipidemia increased the risk of NSCLC in Chinese population.

P1.02-014 HER2 Mutations in Chinese Patients with Non-Small Cell Lung Cancer

ERBB2 (HER2) is a driver gene identified in non-small cell lung cancer (NSCLC). The prevalence, clinicopathology, genetic variability and treatment of HER2-positive NSCLC in Chinese population are unclear. Eight hundred and fifty-nine patients with pathologically confirmed NSCLC were screened for HER2 mutations using Sanger sequencing. Next-generation sequencing (NGS) was performed in positive cases. HER2 amplification was detected with FISH. Overall survival (OS) was evaluated using Kaplan-Meier methods and compared with log-rank tests. Twenty-one cases carrying HER2 mutations were identified with a prevalence of 2.4%. HER2 mutations were more frequently encountered in females, non-smokers and adenocarcinoma. NGS was performed in 19 out of 21 patients, The results showed 16 cases with additional genetic aberrations, most commonly associated with TP53 (n = 6), followed by EGFR (n = 3), NF1 (n = 3), KRAS (n = 2) and other mutations. One patient harbored HER2 amplification (figure 1). Four patients with stage IV received afatinib treatment, and three showed stable disease with a median progression-free survival of 4 months and one patient was diagnosed with progressive disease. No survival difference existed between HER2 positive and negative patients (49.3 months vs.45.0 months, P = 0.150). HER2 mutations represent a distinct subset of NSCLC. NGS showed that HER2 mutations commonly co-existed with other driver genes. Afatinib treatment displayed moderate efficacy in patients with HER2 mutations.

A common CD55 rs2564978 variant is associated with the susceptibility of non-small cell lung cancer.

CD55, as one of key membrane-bound complement-regulatory proteins (mCRPs), is crucial for the progression of various cancers. This study aims to investigate the role of CD55 variants in the development of non-small cell lung cancer (NSCLC). A case-control study, including 706 lung cancer cases and 706 health controls, was conducted in a Chinese population. The odds ratio (OR) and 95% confidence interval (95% CI) were estimated by unconditional logistic regression. We found that significantly higher lung cancer risk was linked with CD55 rs2564978 CC genotype (OR = 1.52, 95% CI = 1.11−2.07) or CT genotypes (OR = 1.34, 95% CI = 1.05−1.71), compared to the TT genotype. Stratified analysis showed that rs2564978 CC was associated with NSCLC risk among males (OR = 1.69, 95% CI = 1.14−2.49) and older subjects (OR = 1.75, 95% CI = 1.08−2.82). When stratified by smoking status, the risk effect of rs2564978 CC was more evident among smokers (OR = 2.01, 95% CI = 1.18−3.43) than non-smokers (OR = 1.30, 95% CI = 0.88−1.90). We also conducted the stratified analysis by NSCLC histological types and found that CD55 rs2564978 CC increased the risk of adenocarcinoma with OR (95% CI) of 1.35 (1.01−1.80). The reporter gene expression driven by rs2564978T-containing CD55 promoter was respectively 1.48-fold, 1.96-fold and 1.93-fold higher than those driven by the rs2564978C-containing CD55 promoter in A549, NCI-H2030 and NCI-H23 cells (P = 0.045, 0.010 and < 0.001). These findings indicate that CD55 rs2564978 polymorphism may contribute to an increased risk of NSCLC in Chinese population.

HER2 mutations in Chinese patients with non-small cell lung cancer.

BackgroundERBB2 (HER2) is a driver gene identified in non-small cell lung cancer (NSCLC). The prevalence, clinicopathology, genetic variability and treatment of HER2-positive NSCLC in Chinese population are unclear.Patients and MethodsEight hundred and fifty-nine patients with pathologically confirmed NSCLC were screened for HER2 mutations using Sanger sequencing. Next-generation sequencing (NGS) was performed in positive cases. HER2 amplification was detected with FISH. Overall survival (OS) was evaluated using Kaplan-Meier methods and compared with log-rank tests.ResultsTwenty-one cases carrying HER2 mutations were identified with a prevalence of 2.4%. HER2 mutations were more frequently encountered in females, non-smokers and adenocarcinoma. NGS was performed in 19 out of 21 patients, The results showed 16 cases with additional genetic aberrations, most commonly associated with TP53 (n = 6), followed by EGFR (n = 3), NF1 (n = 3), KRAS (n = 2) and other mutations. One patient harbored HER2 amplification. Four patients with stage IV received afatinib treatment, and three showed stable disease with a median progression-free survival of 4 months and one patient was diagnosed with progressive disease.ConclusionHER2 mutations represent a distinct subset of NSCLC. NGS showed that HER2 mutations commonly co-existed with other driver genes. Afatinib treatment displayed moderate efficacy in patients with HER2 mutations.

The genetic variations in DNA repair genes ERCC2 and XRCC1 were associated with the overall survival of advanced non-small-cell lung cancer patients.

It was reported that DNA repair can confer cancer cell resistance to therapeutic treatments by activating antiapoptotic cellular defense. We hypothesized that genetic variants of DNA repair genes may be associated with lung cancer prognosis. Seventeen tagging single‐nucleotide polymorphism (tagSNPs) selected from 12 DNA repair genes were genotyped in 280 advanced non‐small‐cell lung cancer (NSCLC) patients by TaqMan assay. The associations of these SNPs and overall survival of advanced NSCLC patients were investigated. Advanced NSCLC patients carrying ERCC2 rs50872 CT+TT genotypes had significantly longer median survival time (MST) and decreased death risk than patients with rs50872 CC genotype [log‐rank P = 0.031; adjusted HR(95% CI) = 0.73 (0.55–0.98), P = 0.033]. These effects were mainly seen among younger patients (≤65 years old) [HR(95% CI) = 0.57 (0.37–0.87), P = 0.010], patients without surgery [HR(95% CI) = 0.68 (0.47–0.98), P = 0.036] but with chemotherapy [HR(95% CI) = 0.64 (0.46–0.91), P = 0.012] or radiotherapy [HR(95% CI) = 0.58 (0.38–0.89), P = 0.013]. Meanwhile, compared to advanced NSCLC patients with rs25487 GG genotype, patients carrying XRCC1 rs25487 GA+AA genotypes had significantly shorter MST (MST = 11.7 vs. 16.7, log‐rank P = 0.048). In addition, advanced NSCLC patients carrying the ERCC2 rs50872 CC in combination with XRCC1 rs25487 GA+AA genotype had the shortest MST (11.2 month) and highest death risk [HR(95% CI) = 1.70 (1.15–2.52), P = 0.008] when compared with those carrying rs50872 CT+TT and rs25487 GG genotype (MST = 22.0 month). The ERCC2 rs50872 T allele was associated with favorable but XRCC1 rs25487 A allele with bad survival for advanced NSCLC in Chinese population, which may offer novel biomarkers for predicting clinical outcomes.

XAB2 tagSNPs contribute to non-small cell lung cancer susceptibility in Chinese population

BackgroundXPA-binding protein 2 (XAB2) interacts with Cockayne syndrome complementation group A (CSA), group B (CSB) and RNA polymerase II to initiate nucleotide excision repair. This study aims to evaluate the association of XAB2 genetic variants with the risk of non-small cell lung cancer (NSCLC) using a tagging approach.MethodsA hospital-based case-control study was conducted in 470 patients with NSCLC and 470 controls in Chinese population. Totally, 5 tag single nucleotide polymorphisms (SNPs) in XAB2 gene were selected by Haploview software using Hapmap database. Genotyping was performed using iPlex Gold Genotyping Asssy and Sequenom MassArray. Unconditional logistic regression was conducted to estimate odd ratios (ORs) and 95 % confidence intervals (95 % CI).ResultsUnconditional logistic regression analysis showed that the XAB2 genotype with rs794078 AA or at least one rs4134816 C allele were associated with the decreased risk of NSCLC with OR (95 % CI) of 0.12 (0.03–0.54) and 0.46 (0.26–0.84). When stratified by gender, we found that the subjects carrying rs4134816 CC or CT genotype had a decreased risk for developing NSCLC among males with OR (95 % CI) of 0.39 (0.18–0.82), but not among females. In age stratification analysis, we found that younger subjects (age ≤ 60) with at least one C allele had a decreased risk of NSCLC with OR (95 % CI) of 0.35 (0.17–0.74), but older subjects didn’t. We didn’t find that XAB2 4134816 C > T variant effect on the risk of NSCLC when stratified by smoking status. The environmental factors, such as age, sex and smoking had no effect on the risk of NSCLC related to XAB2 genotypes at other polymorphic sites.ConclusionsThe XAB2 tagSNPs (rs794078 and rs4134816) were significantly associated with the risk of NSCLC in Chinese population, which supports the XAB2 plays a significant role in the development of NSCLC.

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

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

Tag SNPs of CFI contributed to the susceptibility for non-small cell lung cancer in Chinese population.

Complement factor I (CFI) plays an important role in the development of non-small cell lung cancer (NSCLC). This study aims to examine the association of CFI genetic variants with the risk of developing NSCLC in Chinese population. A hospital-based case-control study was conducted in 470 patients with NSCLC and 470 controls in Chinese population. Totally, 13 tag single nucleotide polymorphisms (tag SNPs) of CFI were selected by Haploview software using the HapMap database. Genotyping was performed using iPLEX Gold Genotyping Assay and Sequenom MassARRAY. The odds ratios (ORs) and 95% confidence interval (95% CI) were calculated by logistic regression model. Our results showed that individuals with rs6822976 GG genotype had a significant decreased risk of NSCLC (OR = 0.64; 95% CI = 0.42-0.98) when compared with rs6822976 AA genotype carriers. We also found that rs7671905 TT genotype exhibited a significant decreased risk of NSCLC compared with CC genotype with OR (95% CI) of 0.55 (0.33-0.91). There was no significant association between other selected SNPs and the risk of NSCLC. When stratified by smoking status, the decreased risk of NSCLC was observed to be associated with the genotype with at least one rs6822976 G allele among non-smokers (OR = 0.66; 95% CI = 0.47-0.93), but not among smokers (OR = 1.01; 95% CI = 0.67-1.53). For CFI rs7671905 polymorphism, the individuals with at least one T allele have a decreased risk of NSCLC with OR (95 % CI) of 0.71 (0.51-0.99), but not among smokers (OR = 0.93; 95% CI = 0.61-1.41). When stratified by age, we found that rs7671905 TT genotype has contributed to the decreased risk of NSCLC among older subjects with OR (95% CI) of 0.46 (0.23-0.95), but not among younger subjects with OR (95% CI) of 0.64 (0.31-1.34) (P(interaction) = 0.03). After stratifying by sex, our study showed that rs7671905 TT genotype was related to the risk of NSCLC among males (OR = 0.53; 95% CI = 0.29-0.98), but not among females (OR = 0.62; 95% CI = 0.25-1.57) (P(interaction) = 0.03). CFI genetic variants played an important role in the development of NSCLC in Chinese population.

Genetic variations in SLC3A2/CD98 gene as prognosis predictors in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is characterized by poor prognosis and only a few molecular markers may be potentially used to predict the risk of progression. This study aims to assess the effects of single nucleotide polymorphisms (SNPs) in the CD98 gene on prognosis of NSCLC patients. We genotyped three potential functional SNPs in CD98 gene using Sequenom iPLEX genotyping system in a cohort of 482 NSCLC patients. Multivariate cox proportional hazards model and Kaplan-Meier curve were used for the survival analysis. The variant-containing genotypes of rs1059292 in 5'-flanking region of CD98 gene were significantly associated with an increased risk of death in the multivariate analysis (Hazard ratio [HR], 1.49; 95% confidence interval [95% CI]: 1.04-2.14 in a dominant model). In stratified analysis, the association remained significant in patients with poor differentiation (HR=1.81, 95% CI=1.01-3.25). In addition, rs1059292 also showed a borderline significant association with T stage (OR=1.49; 95% CI: 0.96-2.35) and N stage (OR=1.53; 95% CI: 0.98-2.39). Functional analysis demonstrated that variant genotype of SNP rs1059292 significantly enhanced the transcription activity of CD98 gene promoter. Our data suggest that genetic variation of rs1059292 in CD98 gene may affect clinical outcome of NSCLC in Chinese population.

Tag SNPs in complement receptor-1 contribute to the susceptibility to non-small cell lung cancer

BackgroundComplement receptor 1 (CR1), the receptor for C3b/C4b complement peptides, plays a crucial role in carcinogenesis. However, the association of genetic variants of CR1 with susceptibility to lung cancer remains unexplored.MethodsThis case-control study included 470 non-small cell lung cancer (NSCLC) patients and 470 cancer-free controls. Based on the Chinese population data from HapMap database, we used Haploview 4.2 program to select candidate tag SNPs. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed by logistic regression to evaluate the association of each tag SNP with NSCLC.ResultsMultivariate regression analysis indicated that the rs7525160 CC genotype was associated with an increased risk of developing NSCLC (OR = 1.52, 95% CI = 1.02-2.28; P = 0.028) compared with the GG genotype. When stratified by smoking status, the risk of NSCLC was associated with the rs7525160 C allele carriers in smokers with OR (95% CI) of 1.72 (1.15-2.79), but not in non-smokers with OR (95% CI) of 1.15 (0.81-1.65). When the interaction between smoking status and rs7525160 G > C variant was analyzed with cumulative smoking dose (pack-year). Similarly, GC or CC genotype carriers have increased risk of NSCLC among heavy smokers (pack-year ≥ 25) with OR (95% CI) of 2.01 (1.26-3.20), but not among light smokers (pack-year <25) with OR (95% CI) of 1.32 (0.81-2.16).ConclusionCR1 rs7525160 G > C polymorphism was associated with an increased risk of developing NSCLC in Chinese population. The association displays a manner of gene-environmental interaction between CR1 rs7525160 tagSNP and smoking status.

Association of miR-502-binding site single nucleotide polymorphism in the 3&amp;prime;-untranslated region of SET8 and TP53 codon 72 polymorphism with non-small cell lung cancer in Chinese population

The objective of this study was to identify whether the miR-502-binding site single nucleotide polymorphism (SNP) in the 3'-untranslated region (3'-UTR) of set domain-containing protein 8 (SET8) and the tumor protein p53 (TP53) codon 72 polymorphism were associated with the risk for non-small cell lung cancer (NSCLC), either independently or jointly, among Chinese people from southern Han. The genotypes of SET8 and TP53 codon 72 polymorphisms of peripheral blood DNA were detected using polymerase chain reaction-restriction fragment length polymorphism and direct DNA sequencing in a case-control study on 164 NSCLC cases and 199 controls. The SET8 TT (odds ratio, OR = 2.173, 95% confidence interval, CI = 1.0454.517) or TP53 GG (OR = 2.579, 95% CI = 1.366-4.870) genotype was associated with an increased risk of NSCLC by comparing with the SET8 CC or TP53 CC genotype, respectively. Similar results were obtained in SET8 recessive model (OR = 2.074, 95% CI = 1.019-4.221, P < 0.05), and the dominant and recessive model of TP53 codon 72 were performed, respectively (OR = 1.809, 95% CI = 1.159-2.825, P < 0.05; OR = 1.933, 95% CI = 1.096-3.409, P < 0.05). In addition, interaction between the SET8 and TP53 polymorphisms increased the risk of NSCLC in a multiply manner, with the OR being 3.032 (95%CI = 1.580-5.816) for subjects carrying both SET8 TT and TP53 GG genotypes. Therefore, the miR-502-binding site SNP in the 3'-UTR of SET8 and the TP53 codon 72 polymorphism may be markers of genetic susceptibility to NSCLC in Chinese population, and there is a possible gene-gene interaction in the incidence of NSCLC.

Association of miR-502-Binding Site Single Nucleotide Polymorphism of SET8 Gene with Non-Small Cell Lung Cancer Risk in Chinese People

Genetic polymorphisms in 3 � -untranslated regions (3 � -UTRs) targeted by miRNAs alter the strength of miRNA binding, with consequences on regulation of target genes thereby affecting the individual’s cancer risk. This study was aimed at investigating the association between the gene polymorphism (rs16917496 C/T) within the miR-502-binding site in the 3 � -UTR of the SET8 and non-small cell lung cancer (NSCLC) risk in Chinese population. The genotypes of SET8 polymorphism of peripheral blood DNA were detected using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct DNA sequencing in a case-control study on 120 NSCLC cases and 164 controls. The CC genotype was associated with a significant decreased risk of NSCLC (P = 0� 011; OR = 0� 307, 95% CI = 0� 119–0.793) by comparing of the TT genotype. The carriers of C allele at the 3 � -UTR polymorphism showed a significantly reduced NSCLC risk (P = 0� 041; OR = 0� 674, 95% CI = 0� 461–0.986) as compared with non-carriers. Therefore, the miR-502-binding site single nucleotide polymorphism (SNP rs 16917496) within the SET8 gene may be a marker of reduced genetic susceptibility to NSCLC in Chinese population.

Comparison of KRAS and EGFR gene status between primary non-small cell lung cancer and local lymph node metastases: implications for clinical practice

BackgroundEpidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) have been widely used for the treatment of non-small cell lung cancer (NSCLC). KRAS and EGFR somatic mutations in NSCLC may predict resistance and responsiveness to TKI, respectively. Nevertheless, most research to date has been conducted on samples from primary tumors. For many patients with advanced disease, their samples can only be obtained from metastases for test. The molecular characteristics of metastasized tumors may be different from those of primary tumors.Materials and methodsMutation status of KRAS and EGFR between primary tumors and local lymph node metastases of 80 Chinese patients with NSCLC were analyzed by direct sequencing. Five of them were given gefitinib as neoadjunvant treatment after the EGFR-TKI sensitive mutations were detected in their biopsies of mediastinal lymph nodes metastases. McNemar's test was used to compare the EGFR and KRAS mutation status between primary tumors and corresponding local lymph node metastases. Data evaluation was carried out with SPSS_13.0 statistical software.ResultsAmong the 160 samples, one primary tumor and seven metastases were identified with KRAS mutations and 21 primary tumors and 26 metastases were found to have EGFR mutations. KRAS and EGFR mutation status was different between primary tumors and corresponding metastases in 6 (7.5%) and 7 (8.75%) patients, respectively. One patient with no TKI sensitive mutations detected in the primary tumor showed disease progression.ConclusionOur results suggest that a considerable proportion of NSCLC in Chinese population showed discrepancy in KRAS and EGFR mutation status between primary tumors and corresponding metastases. This observation may have important implication for the use of targeted TKI therapy in the treatment of NSCLC patients.

Transcriptional inactivation of secreted frizzled-related protein 1 by promoter hypermethylation as a potential biomarker for non-small cell lung cancer

Epigenetic silencing of secreted frizzled-related protein (SFRP) genes, antagonists of the WNT pathway, contributes to the pathogenesis of several cancers including non-small cell lung cancer (NSCLC). We hypothesize that methylation analysis of SFRPs family could improve their use as a panel of biomarkers for diagnosing and staging of NSCLC in China. The expression of four SFRP members (SFRP1, 2, 4, and 5) in NSCLC samples was screened by RT-PCR and quantitative real-time PCR. Only SFRP1 was significantly downregulated in NSCLC, as compared to adjacent normal tissues and benign pulmonary disease tissues (P=0.006). Promoter hypermethylation of SFRP1 was found in 32.1% (25/78) NSCLC specimens and was closely correlated with loss of expression, besides SFRP1 hypermethylation was associated with lymph metastasis (P=0.039) and disease progression within one year (P=0.027). Furthermore, methylated SFRP1 was detected in 28.2% (22/78) of plasma samples from NSCLC patients while only 4% (2/50) in cancer-free controls, and the concordance of SFRP1 methylation status in tumor tissues and corresponding plasmas was satisfactory (P <0.001). In conclusion, epigenetic inactivation of SFRP1 is a common event contributing to lung carcinogenesis and maybe used as a potential biomarker for NSCLC in Chinese population.