Lipid Metabolism Pathway Genes and Lung Cancer: ACADSB rs12220683G>C Is Associated with Better Survival Outcome in Patients with Non-Small Cell Lung Cancer.

INTRODUCTION: Altered lipid metabolism has been reported to be associated with prognosis in multiple cancers. This study aimed to investigate the association of polymorphisms in lipid metabolism pathway genes with survival outcomes in patients with surgically resected non-small cell lung cancer (NSCLC). METHODS: In total, 744 patients with surgically resected NSCLC (380 in the discovery cohort and 364 in the validation cohort) were included in this study. The association between 176 polymorphisms of lipid metabolism pathway genes and the clinical outcomes of NSCLC patients was analyzed. RESULTS: Among the polymorphisms investigated, ACADSB rs10902859G>A was associated with significantly better overall survival (OS) in the discovery, validation, and combined cohorts. ACADSB rs10902859G>A was located in the repressed region and had strong linkage disequilibrium (D' = 1.00 and r2 = 0.94), with rs12220683G>C located in the H3K4me3 peak region, which indicates the presence of active promoters. ACADSB rs12220683G>C was also associated with better OS in the discovery, validation, and combined cohorts (in a dominant model; adjusted hazard ratio [aHR] = 0.53, 95% confidence interval [CI] = 0.30-0.94, p = 0.03; aHR = 0.37, 95% CI = 0.15-0.89, p = 0.03; and aHR = 0.47, 95% CI = 0.29-0.75, p = 0.002, respectively). In vitro luciferase assay demonstrated that the promoter activity of ACADSB was significantly increased in the rs12220683 variant C allele compared with that in the wild G allele (p = 3 × 10-5). CONCLUSION: These results suggest that ACADSB rs12220683G>C increases promoter activity and that increased ACADSB expression may result in better OS in patients with surgically resected NSCLC.

Genetic Polymorphisms in Activating Transcription Factor 3 Binding Site and the Prognosis of Early-Stage Non-Small Cell Lung Cancer.

BACKGROUND: Activating transcription factor 3 (ATF3) plays a significant role in cancer development and progression. We investigated the association between variants in expression quantitative trait loci (eQTLs) within ATF3 binding regions and the prognosis of non-small cell lung cancer (NSCLC) after surgery. METHODS: A total of 772 patients with NSCLC who underwent curative surgery were enrolled. Using a public database (http://galaxyproject.org), we selected 104 single nucleotide polymorphisms (SNPs) in eQTLs in the ATF3 binding regions. The association of those SNPs with disease-free survival (DFS) was evaluated. RESULTS: Among those SNPs, HAX1 rs11265425T>G was associated with significantly worse DFS (aHR = 1.30, 95% CI = 1.00-1.69, p = 0.05), and ME3 rs10400291C>A was associated with significantly better DFS (aHR = 0.66, 95% CI = 0.46-0.95, p = 0.03). Regarding HAX1 rs11265425T>G, the significant association remained only in adenocarcinoma, and the association was significant only in squamous cell carcinoma regarding ME3 rs10400291C>A. ChIP-qPCR assays showed that the two variants reside in active enhancers where H3K27Ac and ATF3 binding occurs. Promoter assays showed that rs11265425 G allele had significantly higher HAX1 promoter activity than T allele. HAX1 RNA expression was significantly higher in tumor than in normal lung, and higher in rs11265425 TG+GG genotypes than in TT genotype. Conversely, ME3 expression was significantly lower in tumor than in normal lung, and higher in rs10400291 AA genotype than in CC+CA genotypes. CONCLUSIONS: In conclusion, this study shows that the functional polymorphisms in ATF3 binding sites, HAX1 rs11265425T>G and ME3 rs10400291C>A are associated with the clinical outcomes of patients in surgically resected NSCLC.

Genetic Variants in One-Carbon Metabolism Pathway Predict Survival Outcomes of Early-Stage Non-Small Cell Lung Cancer.

BACKGROUND: This study was conducted to investigate the association between genetic variants in one-carbon metabolism and survival outcomes of surgically resected non-small cell lung cancer (NSCLC). METHODS: We genotyped 41 potentially functional variants of 19 key genes in the one-carbon metabolism pathway among 750 NSCLC patients who underwent curative surgery. The association between genetic variants and overall survival (OS)/disease-free survival (DFS) were analyzed. RESULTS: Among the 41 single-nucleotide polymorphisms (SNPs) analyzed, 4 SNPs (MTHFD1L rs6919680T>G and rs3849794T>C, MTR rs2853523C>A, and MTHFR rs4846049G>T) were significantly associated with survival outcomes. MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (adjusted hazard ratio [aHR] = 0.73, 95% confidence interval [CI] = 0.54-0.99, p = 0.04) and worse OS (aHR = 2.14, 95% CI = 1.13-4.07, p = 0.02), respectively. MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.41, 95% CI = 1.08-1.83, p = 0.01; and aHR = 1.97, 95% CI = 1.10-3.53, p = 0.02, respectively). When the patients were divided according to histology, the associations were significant only in squamous cell carcinoma (SCC), but not in adenocarcinoma (AC). In SCC, MTHFD1L rs6919680T>G and MTR rs2853523C>A were significantly associated with better OS (aHR = 0.64, 95% CI = 0.41-1.00, p = 0.05) and worse OS (aHR = 2.77, 95% CI = 1.11-6.91, p = 0.03), respectively, and MTHFD1L rs3849794T>C and MTHFR rs4846049G>T were significantly associated with worse DFS (aHR = 1.73, 95% CI = 1.17-2.56, p = 0.01; and aHR = 2.78, 95% CI = 1.12-6.88, p = 0.03, respectively). CONCLUSIONS: Our results suggest that the genetic variants in the one-carbon metabolism pathway could be used as biomarkers for predicting the clinical outcomes of patients with early-stage NSCLC.

Genetic Variant of Notch Regulator DTX1 Predicts Survival After Lung Cancer Surgery.

BACKGROUND: We evaluated the association between genetic variants in the Notch pathway and survival outcomes of patients with surgically resected NSCLC. METHODS: Sixty-four single nucleotide polymorphisms (SNPs) in the Notch pathway genes were evaluated in the discovery study (n = 354) and two sequential validation studies (n = 772 and n = 746, respectively). The association of genotype with overall survival (OS) and disease-free survival (DFS) was evaluated. RESULTS: Of the 64 SNPs analyzed in the discovery study, 9 were significantly associated with OS or DFS. Among them, the association remained significant only for Deltex-1 (DTX1) rs1732786A>G in the first validation study. The second validation study confirmed again the association between DTX1 rs1732786A>G and survival outcomes. In the combined analysis, rs1732786A>G was significantly associated with better OS and DFS (adjusted HR ·aHR· for OS, 0.75; 95% CI 0.64-0.87; P = 0.0002; aHR for DFS, 0.79; 95% CI 0.71-0.89; P = 0.0001). In vitro luciferase assay showed that the rs1732786G allele was associated with higher promoter activity compared to rs1732786A allele. Consistently, relative mRNA expression level of DTX1 showed significant positive correlation with rs1732786 A-to-G change (Ptrend = 0.02) in tumor tissues. CONCLUSIONS: These results suggest that DTX1 rs1732786 is a potential prognostic factor that may have clinical utility in the management of early stage NSCLC.

Functional intronic variant of SLC5A10 affects DRG2 expression and survival outcomes of early-stage non-small-cell lung cancer.

RegulomeDB is a new tool that can predict the regulatory function of genetic variants. We applied RegulomeDB in selecting putative functional variants and evaluated the relationship between these variants and survival outcomes of surgically resected non-small-cell lung cancer. Among the 244 variants studied, 14 were associated with overall survival (P < 0.05) in the discovery cohort and one variant (rs2257609 C>T) was replicated in the validation cohort. In the combined analysis, rs2257609 C>T was significantly associated with worse overall and disease-free survival under a dominant model (P = 2 × 10-5 and P = 0.001, respectively). rs2257609 is located in the SLC5A10 intron, but RegulomeDB predicted that this variant affected DRG2, not SLC5A10 expression. The expression level of SLC5A10 was not different with the rs2257609 genotype. However, DRG2 expression was different according to the rs2257609 genotype (Ptrend   = 0.03) and was significantly higher in tumor than in non-malignant lung tissues (P = 1 × 10-5 ). Luciferase assay also showed higher promoter activity of DRG2 in samples with the rs2257609 T allele (P < 0.0001). rs2257609 C>T affected DRG2 expression and, thus, influenced the prognosis of early-stage non-small-cell lung cancer. This study was approved by the Institutional Review Broad of Kyungpook National University of Hospital (Approval No. KNUMC 2014-04-210-003).

Glucose Transporter 1 Gene Variants Predict the Prognosis of Patients with Early-Stage Non-small Cell Lung Cancer.

BACKGROUND: This study was conducted to investigate whether polymorphisms of glucose transporter 1 (GLUT1) gene are associated with the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. METHODS: Five single nucleotide polymorphisms (SNPs) in GLUT1 were investigated in a total of 354 patients with NSCLC who underwent curative surgery. The association of the SNPs with patients' survival was analyzed. RESULTS: Among the five SNPs investigated, two SNPs (GLUT1 rs3820589T > A and rs4658G > C) were significantly associated with OS in multivariate analyses. GLUT1 rs3820589T > A was associated with significantly better OS (adjusted hazard ratio [aHR] = 0.57, 95% confidence interval [CI] = 0.34-0.94, P = 0.03, under dominant model), and rs4658G > C was associated with significantly worse OS (aHR = 1.91, 95% CI = 1.09-3.33, P = 0.02, under recessive model). In the stratified analysis by tumor histology, the effect of these SNPs on OS was only significant in squamous cell carcinoma but not in adenocarcinoma. When the two SNPs were combined, OS decreased as the number of bad genotypes increased (Ptrend = 4 × 10-3). CONCLUSIONS: This study suggests that genetic variation in GLUT1 may be useful in predicting survival of patients with early stage NSCLC.

Quiescin Sulfhydryl Oxidase 1 (QSOX1) Secreted by Lung Cancer Cells Promotes Cancer Metastasis.

As lung cancer shows the highest mortality in cancer-related death, serum biomarkers are demanded for lung cancer diagnosis and its treatment. To discover lung cancer protein biomarkers, secreted proteins from primary cultured lung cancer and adjacent normal tissues from patients were subjected to LC/MS⁻MS proteomic analysis. Quiescin sulfhydryl oxidase (QSOX1) was selected as a biomarker candidate from the enriched proteins in the secretion of lung cancer cells. QSOX1 levels were higher in 82% (51 of 62 tissues) of lung cancer tissues compared to adjacent normal tissues. Importantly, QSOX1 serum levels were significantly higher in cancer patients (p < 0.05, Area Under curve (AUC) = 0.89) when measured by multiple reaction monitoring (MRM). Higher levels of QSOX1 were also uniquely detected in lung cancer tissues, among several other solid cancers, by immunohistochemistry. QSOX1-knock-downed Lewis lung cancer (LLC) cells were less viable from oxidative stress and reduced migration and invasion. In addition, LLC mouse models with QSOX1 knock-down also proved that QSOX1 functions in promoting cancer metastasis. In conclusion, QSOX1 might be a lung cancer tissue-derived biomarker and be involved in the promotion of lung cancers, and thus can be a therapeutic target for lung cancers.

Polymorphisms in Epithelial-Mesenchymal Transition-Related Genes and the Prognosis of Surgically Treated Non-small Cell Lung Cancer.

BACKGROUND: This study was conducted to determine whether single-nucleotide polymorphisms (SNPs) in EMT-related genes may influence the prognosis of NSCLC after surgery. METHODS: There were 88 SNPs in EMT-related genes evaluated in a discovery set of 376 patients who underwent curative surgery for NSCLC. Significantly, 14 SNPs were evaluated in a validation set of 428 patients. Luciferase assay and RT-PCR were conducted to examine functional relevance of polymorphisms. RESULTS: Fourteen SNPs that were associated with survival outcomes in a discovery set were selected for validation. Among those, two SNPs (FOXF2 rs1711972A>C and HEYL rs784621G>A) were replicated in a validation study. In combined analysis, FOXF2 rs1711972 AC+CC genotype was associated with significantly better overall survival (OS) and disease-free survival (DFS) compared with AA genotype (adjusted hazard ratio [aHR] for OS = 0.67, 95% confidence interval [CI] 0.51-0.88, P = 0.004; and aHR for DFS = 0.77, 95% CI 0.62-0.95, P = 0.01). HEYL rs784621 AA genotype exhibited a significantly worse OS compared with GG+GA genotype (aHR for OS = 2.65, 95% CI 1.63-4.31, P = 8 × 10-5). FOXF2 rs1711972C allele had a significantly increased promoter activity than rs1711972A allele (P = 0.01), and HEYL rs784621A allele had a significantly lower promoter activity than rs784621G allele (P = 0.004). FOXF2 rs1711972A>C was significantly associated with increased FOXF2 mRNA expression. CONCLUSIONS: FOXF2 rs1711972A>C and HEYL rs784621G>A were associated with survival outcomes of surgically treated NSCLC. These SNPs may help to identify patients at high risk of poor disease outcomes.

Polymorphisms in cancer-related pathway genes and lung cancer.

We evaluated the associations between potentially functional variants in a comprehensive list of cancer-related genes and lung cancer in a Korean population.A total of 1969 potentially functional single nucleotide polymorphisms (SNPs) of 1151 genes involved in carcinogenesis were evaluated using an Affymetrix custom-made GeneChip in 610 nonsmall cell lung cancer patients and 610 healthy controls. A replication study was conducted in an independent set of 490 cases and 486 controls. 68 SNPs were significantly associated with lung cancer in the discovery set and tested for replication.Among the 68 SNPs, three SNPs (corepressor interacting with RBPJ 1 (CIR1) rs13009079T>C, ribonucleotide reductase M1 (RRM1) rs1465952T>C and solute carrier family 38, member 4 (SLC38A4) rs2429467C>T) consistantly showed significant associations with lung cancer in the replication study. In combined analysis, adjusted odds ratio for CIR1 rs13009079T>C, RRM1 rs1465952T>C and SLC38A4 rs2429467C>T were 0.69, 0.71 and 0.73, respectively (p=4×10-5, 0.01 and 0.001, respectively) under the dominant model. The relative mRNA expression level of CIR1 was significantly associated with rs13009079T>C genotypes in normal lung tissues (ptrend=0.03).These results suggest that the three SNPs, particularly CIR1 rs13009079T>C, may play a role in the pathogenesis of lung cancer.

The influence of TP53 mutations on the prognosis of patients with early stage non-small cell lung cancer may depend on the intratumor heterogeneity of the mutations.

A large number of studies have evaluated the impact of TP53 mutations on the prognosis of patients with non-small cell lung cancer (NSCLC); however, the results of these studies are still controversial. Recently, considerable intratumor heterogeneity for genetic alterations has been demonstrated in various human cancers, including lung cancer. In the present study, we evaluated TP53 mutations in NSCLCs by direct sequencing and observed remarkable variation in the values of relative intensity (RI, the height of the peak of mutated allele/the height of the peak of non-mutated allele) of the mutations. We also examined whether the RI values were associated with intratumor heterogeneity of TP53 mutations. In addition, we evaluated the relationship between TP53 mutations and survival outcome. The patients with a TP53 mutation did not have significantly worse survival compared to those without the mutation. However, when tumors with a TP53 mutation were categorized into two groups, those with a low and those with a high RI, the latter group had significantly worse survival compared to those with wild-type TP53 (adjusted hazard ratio = 2.58, 95% confidence interval = 1.21-5.48, P = 0.01), whereas the former group did not. These results suggest that intratumor genetic heterogeneity may be an important factor in determining the role of TP53 mutations on the prognosis of NSCLC patients.

Clinical characteristics and course of pulmonary artery stump thrombosis following lung cancer surgery: A retrospective study from tertiary care hospital.

The data regarding pulmonary artery stump thrombosis (PAST) after lung cancer surgery are insufficient. The aim of the present study was to evaluate the incidence, clinical characteristics, and prognosis of PAST. We retrospectively investigated the incidence and clinical characteristics of PAST among patients who underwent lung resection for lung cancer at 2 institutions. We compared the clinical parameters between PAST and pulmonary embolism (PE) and examined the clinical course of patients with PAST. Of the 1885 patients, PAST was found in 36 patients (1.9%). Right lower lobectomy (n = 13) and middle-lower bilobectomy (n = 9) were the most common types of surgery. The median time interval from lung resection to the detection of PAST was 3.8 months. Immobilization and a history of cerebrovascular disease were not observed in the PAST group. Most of the patients with PAST (91.7%) were diagnosed incidentally, whereas many patients with PE (75.9%) were symptomatic at the time of diagnosis. During the follow-up, one patient (2.8%) had contralateral PE complications. However, no patients in the PAST group experienced pulmonary thromboembolism-related in-hospital death or adverse outcomes. There was no difference in the prognosis of patients with PAST according to the administration of anticoagulation. PAST was rarely detected in lung cancer patients on follow-up chest computed tomography after lung resection. Patients with PAST were asymptomatic in most cases and had relatively favorable clinical outcomes. However, these patients are at risk of contralateral PE, despite its rarity.

Regulating POLR3G by MicroRNA-26a-5p as a promising therapeutic target of lung cancer stemness and chemosensitivity.

Cancer stem cells (CSCs) identified in lung cancer exhibit resistance to chemotherapy, radiotherapy, and targeted therapy. Therefore, a technology for controlling CSCs is needed to overcome such resistance to cancer therapy. Various evidences about the association between epithelial-mesenchymal transition related transcriptomic alteration and acquisition of CSC phenotype have been proposed recently. Down-regulated miR-26a-5p is closely related to mesenchymal-like lung cancer cell lines. These findings suggest that miR-26a-5p might be involved in lung cancer stemness. RNA polymerase III subunit G (POLR3G) was selected as a candidate target of miR-26a-5p related to cancer stemness. It was found that miR-26a-5p directly regulates the expression of POLR3G.Overexpression of miR-26a-5p induced a marked reduction of colony formation and sphere formation. Co-treatment of miR-26a-5p and paclitaxel decreased cell growth, suggesting that miR-26a-5p might play a role as a chemotherapy sensitizer. In the cancer genome atlas data, high miR-26a-5p and low POLR3G expression were also related to higher survival rate of patients with lung adenocarcinoma. These results suggest that miR-26a-5p can suppress lung cancer stemness and make cancer cell become sensitive to chemotherapy. This finding provides a novel insight into a potential lung cancer treatment by regulating stemness.

Genetic variants in key necroptosis regulators predict prognosis of non-small cell lung cancer after surgical resection.

BACKGROUND: Necroptosis is a regulated inflammatory cell death which plays a significant role in cancer development and progression. In this study, we evaluated whether genetic variants in key regulators of necroptosis may affect survival outcome of non-small cell lung cancer (NSCLC) patients after surgical resection. METHODS: A total of 674 patients who underwent curative surgery were included. Fifteen genetic variants in key regulators of necroptosis (RIPK1, RIPK3, and MLKL) were selected. The association of these variants with survival outcomes was evaluated. RESULTS: Two variants, RIPK1 rs17548629C > T and MLKL rs877375G > C, were associated with better overall survival and disease-free survival in multivariate analyses. When the patients were divided according to histology, the associations were significant only in adenocarcinoma, but not in squamous cell carcinoma. RIPK1 rs17548629 C-to-T change was associated with significantly increased luciferase activity by modulating the binding of miR-642a. Promoter assays showed a significantly increased promoter activity in MLKL rs877375C allele compared to G allele. Consistently, the mRNA expression level of RIPK1 and MLKL showed significant positive correlation with RIPK1 rs17548629C-to-T and MLKL rs877375G-to-C changes. CONCLUSION: Two genetic variants in key regulators in necroptosis, RIPK1 rs17548629C > T and MLKL rs877375G > C, may be used as biomarkers to predict survival outcomes in surgically resected NSCLC patients.

AKT1 polymorphisms and survival of early stage non-small cell lung cancer.

BACKGROUND AND OBJECTIVES: This study was conducted to investigate the impact of polymorphisms in the AKT1 gene on the survival of early stage non-small cell lung cancer (NSCLC) patients. METHODS: Three hundred and ten patients with surgically resected NSCLC were enrolled. The rs3803300, rs1130214, rs3730358, rs1130233, and rs2494732 single nucleotide polymorphisms (SNPs) in the AKT1 gene were investigated. The genotype and haplotype associations with overall survival (OS) and disease free survival (DFS) were analyzed. RESULTS: The three SNPs (rs3803300, rs1130214, and rs2494732) were significantly associated with survival outcomes on multivariate analysis. When the three SNPs were combined, OS and DFS were decreased in a dose-dependent manner as the number of bad genotypes increased (P(trend) = <1.0 × 10(-4) and 0.001, respectively). Patients with 2 bad genotypes had a significantly worse OS and DFS compared with those with 0 bad genotypes (adjusted hazard ratio (HR) = 3.08, 95% confidence interval (CI) = 1.61-5.89, P = 0.001; and adjusted HR = 2.04, 95% CI = 1.22-3.43, P = 0.01). CONCLUSIONS: These results suggest that the AKT1 polymorphisms could be used as prognostic markers for the patients with early-stage NSCLC.

EML4-ALK fusion gene in Korean non-small cell lung cancer.

A fusion gene between echinoderm microtubule-associated protein-like 4 (EML4) and the anaplastic lymphoma kinase (ALK) has been identified in non-small cell lung cancers (NSCLCs). Although a few studies have evaluated EML4-ALK fusion genes in Korean NSCLCs, the prevalence of different EML4-ALK fusion variants has yet to be clearly assessed. Herein, we have examined the profiles of EML4-ALK fusion gene variants in Korean patients of NSCLCs. EML4-ALK fusion genes have been detected in 10 (6.0%) of 167 patients of NSCLCs and in 9 (7.4%) of 121 patients of adenocarcinoma. Of the 10 patients with fusion genes identified, 8 (80%) were E13;A20 (variant 1) and 2 (20%) were E6;A20, with an additional 33-bp sequence derived from intron 6 of EML4 (variant 3b). These results indicate that the profiles of EML4-ALK fusion gene variants in Korean patients of NSCLC may differ from those in other ethnic populations. Herein, we describe for the first time the profiles of EML4-ALK fusion variants of Korean patients with NSCLCs.

Pulmonary vein stump thrombosis after lung resection for lung cancer: clinical features and outcome.

Pulmonary vein stump thrombosis (PVST) is uncommonly encountered postoperative in-situ thrombosis in the stump of pulmonary veins after lung resection. Data regarding the incidence and clinical behaviour of PVST are scarce. Thus, this study aims to investigate the incidence, clinical characteristics and outcome of PVST after lung resection in patients with lung cancer. Follow-up enhanced chest computed tomography (CT) scans acquired after the surgery were retrospectively reviewed to determine PVST presence for patients with lung cancer who underwent lung resection in two tertiary referral centres. Out of the 1885 patients with lung cancer who underwent lobectomy or more extensive lung resection, PVST was observed in 37 patients (2.0%) on their follow-up chest CT. Most stump thrombi were observed in the left superior pulmonary vein [35 (94.6%)] and in patients who underwent left upper lobectomy [34 (91.9%)]. At the last CT follow-up of each patient, 33 (89.2%) exhibited complete resolution, three partial resolution and one stabilization. Eleven (29.7%) patients received anticoagulant therapy after the diagnosis. The rate of complete PVST resolution did not differ significantly between the anticoagulation and nonanticoagulation groups. None of the PVST patients experienced systemic embolic events, regardless of anticoagulation. The PVST incidence diagnosed at routine chest CT follow-up following lung cancer surgery was 2%. PVST was characterized by a benign clinical course without progression and systemic embolization, regardless of anticoagulation. However, further studies are required to determine individualized therapeutic strategies, including anticoagulation.

Genetic variants in LKB1/AMPK/mTOR pathway are associated with clinical outcomes of chemotherapy in non-small cell lung cancer.

This study was conducted to investigate the relationship between genetic variants in LKB1/AMPK/mTOR pathway and treatment outcomes of patients with non-small cell lung cancer (NSCLC) treated with chemotherapy. A total of 379 patients with NSCLC who underwent first-line paclitaxel-cisplatin chemotherapy was enrolled. The associations between 19 single nucleotide variants (SNVs) in the LKB1/AMPK/mTOR pathway and the chemotherapy response and overall survival (OS) were analyzed. Among the SNVs analyzed, AKT1 rs2494750G>C and TSC1 rs2809244C>A were associated with clinical outcomes after chemotherapy in multivariate analyses. The AKT1 rs2494750G>C was significantly associated with a better response to chemotherapy (adjusted odds ratio [aOR]: 1.92, 95% confidence interval [CI]: 1.02-3.62, p = 0.04). The TSC1 rs2809244C>A were significantly associated with better OS (adjusted hazard ratio [aHR]: 0.79, 95% CI: 0.62-0.99, p = 0.04). When stratified by tumor histology, AKT1 rs2494750G>C exhibited a significant association with the chemotherapy response only in adenocarcinoma and TSC1 rs2809244C>A was also significantly associated with OS only in adenocarcinoma. This result suggests that the AKT1 rs2494750G>C and TSC1 rs2809244 C>A may be useful for predicting the clinical outcome of first-line paclitaxel-cisplatin chemotherapy in NSCLC.

Epigenetic readers and lung cancer: the rs2427964C>T variant of the bromodomain and extraterminal domain gene BRD3 is associated with poorer survival outcome in NSCLC.

Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that regulate gene expression. We investigated whether variants in BET genes are associated with survival outcomes for lung cancer. To do this, the associations between 77 variants in BET family genes and survival outcomes were analyzed in 773 non-small-cell lung cancer (NSCLC) patients who underwent surgery (349 and 424 patients in the discovery and validation cohorts, respectively). We found that six variants were significantly associated with overall survival (OS) in the discovery cohort, and one variant (rs2506711C>T) was replicated in the validation cohort. BRD3 rs2506711C>T is located in the repressed area and has a strong linkage disequilibrium with rs2427964C>T in the promoter region. BRD3 rs2427964C>T was significantly associated with worse OS in the discovery cohort, validation cohort, and combined analysis. In a luciferase assay, promoter activity in the BRD3 rs2427964 T allele was significantly higher than that in the BRD3 rs2427964 C allele, which selectively bound with the transcriptional repressor SIN3A. Knockdown of BRD3 with BRD3-specific siRNA decreased the proliferation and migration of lung cancer cells while also increasing the rate of apoptosis. These results suggest that BRD3 rs2427964C>T increases BRD3 expression through increased promoter activity, which is associated with poor prognosis for lung cancer.

Dual roles of a variable number of tandem repeat polymorphism in the TERT gene in lung cancer.

This study was conducted to determine the impact of a functional tandem repeat minisatellite (MNS16A) polymorphism in the telomerase reverse transcriptase (TERT) gene on the risk of lung cancer, as well as on survival of patients with non-small-cell lung cancer (NSCLC). The effect of the MNS16A variable number of tandem repeat (VNTR) polymorphism on the risk of lung cancer was evaluated in a case-control study that consisted of 937 lung cancer patients and 943 healthy controls. The effect of the polymorphism on survival outcome was evaluated in 703 patients with surgically resected NSCLC. Compared with the VNTR-302 allele, the VNTR-243 allele was associated with a significantly increased risk of lung cancer (adjusted odds ratio, 1.55; 95% confidence interval [CI], 1.07-2.25; P = 0.02). In addition, the genotypes carrying at least one VNTR-243 allele were associated with a significantly increased risk of lung cancer compared with the genotypes with no VNTR-243 allele (adjusted odds ratio, 1.61; 95% CI, 1.09-2.38; P = 0.02). In contrast to the effect of the polymorphism on the risk of lung cancer, the genotypes carrying at least one VNTR-243 allele were associated with a significantly better overall survival in patients with surgically resected NSCLC (adjusted hazard ratio, 0.51; 95% CI, 0.28-0.93; P = 0.03). These findings suggest that the MNS16A VNTR polymorphism in the TERT gene has dual, conflicting roles in lung carcinogenesis. This polymorphism may increase the risk of lung cancer development, and may improve survival in lung cancer patients.

Comparison of costs for video-assisted thoracic surgery lobectomy and open lobectomy for non-small cell lung cancer.

BACKGROUND: To promote the broad use of video-assisted thoracic surgery (VATS) for lobectomy (VATSL) in the management of lung cancer, it should be proved cost-effective, especially in the current cost-sensitive climate. This study evaluated and compared the costs of VATSL and open lobectomy (OL) and analyzed how the surgeon's experience level with VATSL affected the cost. METHODS: In this study, 86 patients in a VATSL group and 97 patients in an OL group underwent surgery for lung cancer. Cost comparisons were performed for the VATSL and OL groups between patients who had no complications and patients with and without complications according to tumor location and the learning period of the surgeon. RESULTS: Postoperative complications occurred for 56 patients (30.6%) (14 VATSL vs 42 OL patients; p < 0.05). Patients who underwent VATSL had significant reductions in both chest tube duration (5.4 vs 9.1 days; p = 0.000) and length of hospital stay (7.1 vs 12.0 days; p = 0.000). The mean operation time for VATSL was not significantly longer than for OL (145.8 vs 136.4 min; p = 0.782). The total hospital cost (i.e., that paid by the patient and national insurance combined) was lower for VATSL than for OL according to comparisons both among all patients ($5,391 vs $5,593, respectively) and among only noncomplicated patients ($4,684 vs $4,769, respectively). In terms of tumor location, the total hospital cost for the VATSL group was lower than for the OL group when the surgery was performed on the right lower lobe (RLL), left upper lobe (LUL), and left lower lobe (LLL). The costs were not significantly different between the two learning periods of the surgeons, except for the cost of anesthesia. CONCLUSIONS: In Korea, VATSL for lung cancer had lower complication rates, shorter hospital stays, and lower total hospital costs than OL.