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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., In this study, we investigated the association of BET gene variants with survival of patients with non‐small‐cell lung cancer (NSCLC). We observed that the rs2427964C>T SNP in the BRD3 promoter region was associated with poorer survival outcome. BRD3 promoter activity was higher in rs2427964_T than in rs2427964_C, which selectively bound with the transcriptional repressor SIN3A. Additionally, BRD3 silencing decreased the proliferation and migration of NSCLC cells. Our data suggest that elevated BRD3 expression regulated by rs2427964C>T leads to reduced overall survival in patients with NSCLC.

Neurogenic differentiation factor 1 (NEUROD1) is frequently overexpressed in small-cell lung cancer (SCLC). NEUROD1 plays an important role in promoting malignant behavior and survival. In this study, we evaluated the association between putative functional polymorphisms in 45 NEUROD1 target genes and chemotherapy response and survival outcomes in 261 patients with SCLC. Among the 100 single nucleotide polymorphisms (SNPs) studied, two were significantly associated with both chemotherapy response and overall survival (OS) of patients with SCLC. The SNP rs3806915C>A in semaphorin 6A (SEMA6A) gene was significantly associated with better chemotherapy response and OS (P = 0.04 and P = 0.04, respectively). The SNPrs11265375C>T in nescient helix-loop helix 1 (NHLH1) gene was also associated with better chemotherapy response and OS (P = 0.04 and P = 0.02, respectively). Luciferase assay showed a significantly higher promoter activity of SEMA6A with the rs3806915 A allele than C allele in H446 lung cancer cells (P = 4 × 10-6). The promoter activity of NHLH1 showed a significantly higher with the rs11265375 T allele than C allele (P = 0.001). These results suggest that SEMA6A rs3806915C>A and NHLH1 rs11265375C>T polymorphisms affect the promoter activity and expression of the genes, which may affect the survival outcome of patients with SCLC.

Objective: This study was conducted to investigate the association between genetic variants in histone modification regions and clinical outcomes of PEM chemotherapy in patients with lung adenocarcinoma. Methods: Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The associations of 279 SNPs with chemotherapy response and overall survival (OS) were analyzed in 314 lung adenocarcinoma patients who underwent PEM chemotherapy. Results: Among the SNPs investigated, 18 were significantly associated with response to chemotherapy, while 28 with OS. Of these SNPs, rs549794A>G in an enhancer which is expected to regulate the expression of ribosomal protein S3 (RPS3) gene was significantly associated with both worse response to chemotherapy and worse OS (adjusted odds ratio = 0.59, 95% CI = 0.36–0.97, p = 0.04; adjusted hazard ratio = 1.44, 95% CI = 1.09–1.91, p = 0.01, respectively). Previous studies suggested that RPS3, a multi-functional protein with various extraribosomal activities, may play a role in chemotherapy resistance. Therefore, it is postulated that rs549794-induced change in the expression level of RPS3 may affect the response to PEM chemotherapy and consequently the survival outcomes in lung adenocarcinoma patients. Conclusion: This study suggests that genetic variants in the histone modification regions may be useful for the prediction of clinical outcomes of PEM chemotherapy in advanced lung adenocarcinoma.

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.

Background/aims Genome wide and candidate gene association studies have identified polymorphisms associated with the risk of lung cancer in never-smokers. This study was conducted to evaluate the association between 11 polymorphisms identified in female never smokers and the lung cancer risk in male smokers. Methods This study included 714 lung cancer patients and 626 healthy controls. The polymorphisms were genotyped using SEQUENOM MassARRAY iPLEX assay or Taq-Man assay. Results Two polymorphisms were associated with the risk of lung cancer in male smokers, as in female never smokers. Male smokers carrying the rs4975616 variant allele had a significantly decreased risk of lung cancer (in a codominant model: odds ratio, 0.77; 95% confidence interval, 0.61 to 0.96; p = 0.02). The rs9387478 polymorphism also reduced lung cancer risk in male smokers (in a codominant model: odds ratio, 0.85; 95% confidence interval, 0.73 to 0.997; p = 0.046). In a stratified analysis, the association between these polymorphisms and the risk of lung cancer was predominant in lighter smokers and for cases of adenocarcinoma. Conclusion These results suggest that a subset of polymorphisms known to be associated with the risk of lung cancer in female never smokers is also associated with the risk of lung cancer in male smokers.

BACKGROUND Achaete-scute homolog 1 (ASCL1) is a basic helix-loop-helix transcription factor and is essential in the differentiation of neuroendocrine cells and neural tissues. ASCL1 is frequently overexpressed in small cell lung cancer (SCLC) and plays a crucial role in the pathogenesis of SCLC. METHODS This study was conducted to identify the association between single nucleotide polymorphisms (SNPs) in ASCL1 target genes and clinical outcomes of patients with SCLC after chemotherapy. A total of 261 patients diagnosed with SCLC were enrolled in this study. The association between 103 SNPs in 58 ASCL1 target genes and the response to chemotherapy and survival of patients with SCLC were analyzed. RESULTS Among the 103 SNPs, 10 SNPs were significantly associated with the response to chemotherapy, and 19 SNPs were associated with OS in multivariate analyses. Among these, Dopa Decarboxylase (DDC) rs12666409A>T was significantly associated with both a worse response to chemotherapy and worse OS (adjusted odds ratio [aOR] = 0.40, 95% CI = 0.18-0.90, P = 0.03; adjusted hazard ratio [aHR] = 1.52, 95% CI = 1.10-2.10, P = 0.01, respectively, under a dominant model). In a stage-stratified analysis, the association was significant only in the extensive disease subgroup (aOR = 0.19, 95% CI = 0.06-0.60, P = 0.01; aHR = 1.73, 95% CI = 1.16-2.56, P = 0.01, respectively, under a dominant model), but not in the limited disease subgroup. CONCLUSION The results of our study suggest that DDC rs12666409A>T may be useful markers for predicting the clinical outcomes of patients with SCLC undergoing chemotherapy.

Ji Eun Park,1,* Mi Jeong Hong,2,3,* Shin Yup Lee,1,4 Jang Hyuck Lee,2,4 Jin Eun Choi,2,3 Hyo-Gyoung Kang,2,3 Sook Kyung Do,2,3 Ji Yun Jeong,5 Kyung Min Shin,6 Won Kee Lee,7 Sun Ha Choi,1 Yong Hoon Lee,1 Hye won Seo,1 Seung Soo Yoo,1 Jaehee Lee,1 Seung Ick Cha,1 Chang Ho Kim,1 Jae Yong Park1,2 1Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 2Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 3Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 4BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea; 5Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 6Department of Radiology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; 7Department of Medical Informatics, School of Medicine, Kyungpook National University, Daegu, Republic of Korea*These authors contributed equally to this workCorrespondence: Shin Yup Lee; Jae Yong ParkDepartment of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of KoreaTel +82-53-200-2632Fax +82-53-200-2027Email shinyup@knu.ac.kr; jaeyong@knu.ac.krIntroduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have represented the prototype of targeted therapy in NSCLC. Patients with EGFR-mutant lung adenocarcinoma extract an extraordinary clinical benefit from EGFR-TKIs. However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual’s response to TKIs. We investigated whether genetic variants in miRNA binding sites are associated with the clinical outcome of EGFR-TKIs in lung adenocarcinoma patients.Methods: One hundred SNPs at miRNA binding sites in cancer-related genes were selected for the analysis using the crosslinking, ligation and sequencing of hybrids (CLASH) and CancerGenes database. qRT-PCR and luciferase assays were conducted to evaluate the functional relevance of the SNPs.Results: NUP62 rs9523A>G were significantly associated with worse response to EGFR-TKIs, overall survival (OS), and progression-free survival (PFS). The other three SNPs (DVL2 rs2074216G>A, ARF1 rs11541557G>T, and UHRF1 rs2261988C>A) were significantly associated with worse OS and PFS. The rs9523A>G was significantly associated with decreased NUP62 expression in tumor tissues. In addition, a significantly decreased luciferase activity was noted in NUP62 rs9523 G allele compared to A allele.Conclusion: Genetic variants in miRNA binding sites, especially NUP62 rs9523A>G, may be useful in predicting the clinical outcomes of EGFR-mutant lung adenocarcinoma patients treated with EGFR-TKIs.Keywords: lung adenocarcinoma, EGFR-TKI, clinical outcome, miRNA binding site, polymorphism

We investigated the association between genetic variants in the histone modification regions and the prognosis of lung adenocarcinoma after curative surgery. Potentially functional SNPs were selected using integrated analysis of ChIP-seq and RNA-seq. The SNPs were analyzed in a discovery set (n=166) and a validation set (n=238). The associations of the SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. A total of 279 SNPs were selected for genotyping. Among these, CAPN1 rs17583C>T was significantly associated with better OS and DFS (P = 0.001 and P = 0.007, respectively), and LINC00959 rs4751162A>G was significantly associated with worse DFS (P = 0.008). Luciferase assays showed a significantly lower promoter activity of CAPN1 in the rs17583 T allele than C allele (P = 0.008), and consistently the CT+TT genotypes had significantly lower CAPN1 expression than CC genotype (P = 0.01) in clinical samples. The rs4751162 G allele had higher promoter activity of GLRX3 than A allele (P = 0.05). The motif analyses and ChIP-qPCR confirmed that the variants are located in the active promoter/enhancer regions where transcription factor binding occurs. This study showed that genetic variants in the histone modification regions could predict the prognosis of lung adenocarcinoma after surgery.

This study was conducted to investigate the impact of genetic variants of immune checkpoint genes on the treatment outcome in small cell lung cancer (SCLC). In the present study, 261 platinum doublet-treated SCLC patients were enrolled. A total of 96 polymorphisms in 33 immune checkpoint-related genes were selected, and their association with chemotherapy response and survival outcomes were analyzed. Among the polymorphisms studied, CD155 rs1058402G > A (Ala67Thr, A67T) and CD226 rs763361C > T (Gly307Ser, G307S) were significantly associated with SCLC treatment outcome. The rs1058402G > A had a worse chemotherapy response and overall survival (under a dominant model, adjusted odds ratio [aOR] = 0.52, 95% confidence interval [CI] = 0.27–0.99, P = 0.05; adjusted hazard ratio [aHR] = 1.55, 95% CI = 1.12–2.14, P = 0.01, respectively). The rs763361C > T had better chemotherapy response and overall survival (under a dominant model, aOR = 2.03, 95% CI = 1.10–3.75, P = 0.02; aHR = 0.69, 95% CI = 0.51–0.94, P = 0.02, respectively). When the rs1058402GA/AA and rs763361CC genotypes were combined, the chemotherapy response and overall survival were significantly decreased as the number of bad genotypes increased (aOR = 0.52, 95% CI = 0.33–0.81, Ptrend = 0.004; aHR = 1.48, 95% CI = 1.19–1.84, Ptrend = 4 × 10−4, respectively). The 3-D structural model showed that CD155 A67T created a new hydrogen bond and structural change on CD155. These changes resulted in extending the distance and losing the hydrogen bonds between CD155 and CD226, thus weakening CD155/CD226 binding activity. In conclusion, CD155 rs1058402G > A and CD226 rs763361C > T may be useful for predicting the clinical outcomes of SCLC patients after chemotherapy.

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.

Deltex‐1 (DTX1) is a negative regulator of the Notch signaling pathway. Here, we investigated the clinical effect of DTX1 rs1732786A > G, which is associated with better prognosis in patients with early‐stage non‐small cell lung cancer (NSCLC), in 261 patients with small cell lung cancer (SCLC). DTX1 rs1732786A > G was associated with a significantly worse chemotherapy response and lower overall survival in the codominant model (odds ratio = 0.42, 95% confidence interval [CI]: 0.26–0.66, P = 2 × 10−4; hazard ratio = 1.47, 95% CI: 1.17–1.84, P = 0.001, respectively). An in vitro luciferase assay was performed, and the 1732786G allele demonstrated significantly higher promoter activity than the 1732786A allele (P = 2 × 10−7). In summary, DTX1 rs1732786A > G was associated with poor prognosis in patients with SCLC as opposed to patients with NSCLC. Key points Significant findings of the study DTX1 rs1732786A > G was associated with better prognosis in patients with early‐stage non‐small cell lung cancer (NSCLC) in our previous study. What this study adds DTX1 rs1732786A > G was associated with a significantly worse chemotherapy response and lower overall survival in small cell lung cancer (SCLC)., DTX1 rs1732786A>G was associated with better prognosis in patients with early‐stage non‐small cell lung cancer, in the previous study. DTX1 rs1732786A>G was associated with a significantly worse chemotherapy response and lower overall survival in small cell lung cancer.

Background: Accumulating evidence suggests that necroptosis, or programmed necrotic cell death, may play a significant role in cancer. We evaluated the expression of key molecules in necroptosis and their association with clinical features and prognosis in NSCLC. Methods: A total of 253 NSCLC patients (96 squamous cell carcinoma [SCC] cases and 157 adenocarcinoma [AC] cases) who underwent curative resection were included. Tumor tissues and corresponding normal tissues were investigated for relative mRNA expression levels of RIPK1, RIPK3, and MLKL. Difference in disease free survival (DFS) was analyzed according to the expression levels of these molecules in tumor tissues. Results: NSCLC tissues had significantly lower expression of RIPK1, RIPK3, and MLKL than normal tissues (P = 1 x 10-4, P = 8 x 10-6, and P = 4 x 10-8, respectively). In subgroup analysis, SCCs had significantly lower RIPK1, RIPK3, and MLKL expression (P = 5 x 10-4, P = 3 x 10-15, P = 1 x 10-5, respectively), and ACs had significantly lower RIPK1 and MLKL expression (P = 0.01 and P = 6 x 10-4, respectively) than normal tissues. Low expression of RIPK1, RIPK3, and MLKL in tumors was associated with a worse DFS (HR = 1.71, P = 0.01; HR = 1.53, P = 0.04; and HR = 1.53, P = 0.04, respectively) in a multivariate analysis. In SCC, none of the RIPK1, RIPK3, and MLKL expression was significantly associated with DFS. However, in AC, low expression of RIPK1, RIPK3, and MLKL was significantly associated with worse DFS (HR = 1.67, P = 0.03; HR = 1.70, P = 0.03; and HR = 1.81, P = 0.02, respectively). Conclusions: Key regulatory genes in necroptosis, RIPK1, RIPK3, and MLKL, were downregulated in NSCLC, and their lower expression in NSCLC may be used to predict early recurrence after curative resection, especially in AC.

This study was conducted to investigate the associations between polymorphisms of genes involved in the LKB1 pathway and the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Twenty-three single nucleotide polymorphisms (SNPs) in the LKB1 pathway were investigated in 782 patients with NSCLC who underwent curative surgery. The association of SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. Among the 23 SNPs investigated, TSC2 rs30259G > A was associated with significantly worse OS and DFS (adjusted hazard ratio for OS 1.88, 95% confidence interval 1.21-2.91, P = 0.005; adjusted hazard ratio for DFS 1.65, 95% confidence interval 1.15-2.38, P = 0.01, under codominant models, respectively). Subgroup analysis showed that SNPs were significantly associated with survival outcomes in squamous cell carcinoma, ever-smokers, and stage I, but not in adenocarcinoma, never-smokers, and stage II-IIIA. The results suggest that TSC2 rs30259G > A may be useful to predict prognosis in patients with NSCLC, especially squamous cell carcinoma, after curative surgery.

This study was conducted to investigate the associations between polymorphisms of genes involved in the LKB1 pathway and the prognosis of patients with non‐small cell lung cancer (NSCLC) after surgical resection. Twenty‐three single nucleotide polymorphisms (SNPs) in the LKB1 pathway were investigated in 782 patients with NSCLC who underwent curative surgery. The association of SNPs with overall survival (OS) and disease‐free survival (DFS) were analyzed. Among the 23 SNPs investigated, TSC2 rs30259G > A was associated with significantly worse OS and DFS (adjusted hazard ratio for OS 1.88, 95% confidence interval 1.21–2.91, P = 0.005; adjusted hazard ratio for DFS 1.65, 95% confidence interval 1.15–2.38, P = 0.01, under codominant models, respectively). Subgroup analysis showed that SNPs were significantly associated with survival outcomes in squamous cell carcinoma, ever‐smokers, and stage I, but not in adenocarcinoma, never‐smokers, and stage II–IIIA. The results suggest that TSC2 rs30259G > A may be useful to predict prognosis in patients with NSCLC, especially squamous cell carcinoma, after curative surgery.

Background We conducted this study to identify regulatory variants in cancer-related pathway genes which can predict clinical outcomes of chemotherapy in advanced NSCLC, using a comprehensive list of regulatory SNPs prioritized by RegulomeDB. Methods A total of 509 potentially functional SNPs in cancer-related pathway genes were evaluated. The SNPs were analyzed in a discovery set (n = 198), and an independent validation set (n = 181). The associations of the SNPs with chemotherapy response and overall survival (OS) were analyzed. Results In the discovery set, 95 SNPs were significantly associated with clinical outcomes. Among the 95 SNPs, only rs10414193A > G in the intronic region of ARID3A, an eQTL for LKB1, was consistently associated with chemotherapy response and OS in the validation set. In combined analysis, the rs10414193A > G was significantly associated with worse response to chemotherapy (adjusted odds ratio = 0.63, 95% CI = 0.47–0.85, P = 0.002), and with worse OS (adjusted hazard ratio = 1.25, 95% CI = 1.08–1.45, P = 0.004). Luciferase assay showed a significantly higher LKB1 promoter activity associated with rs10414193G allele compared with rs10414193A allele (P = 0.0009). Conclusions Our results suggest that rs10414193A > G may be useful for the prediction of clinical outcomes of chemotherapy in advanced NSCLC.

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 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 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).

A high-throughput mapping method of RNA–RNA interactions by crosslinking, ligation, and sequencing of hybrids (CLASH) can not only provide information about canonical but also non-canonical interactions. We evaluated the associations between variants in microRNA target sites using CLASH data and survival outcomes of 782 early-stage non-small cell lung cancer (NSCLC) patients who underwent curative surgical resection. Among the 100 variants studied, two variants showed significant association with survival outcomes. The POLR2A rs2071504 C > T variant was associated with poor overall and disease-free survival under a dominant model (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.08–1.88; P = 0.01 and HR 1.34, 95% CI 1.08–1.67; P = 0.01, respectively). Patients carrying the NR2F6 rs2288539 TT genotype showed significantly better overall survival than those with the NR2F6 rs2288539 CC or CT genotypes (HR 0.13, 95% CI 0.02–0.90; P = 0.04). These findings suggest that POLR2A rs2071504 C > T and NR2F6 rs2288539 C > T can influence prognosis in early-stage NSCLC patients.

Objective: This study was conducted to investigate whether polymorphisms in glycolysis-related genes are associated with clinical outcomes of patients with advanced-stage non-small cell lung cancer (NSCLC) undergoing chemotherapy. Methods: A total of 377 patients with NSCLC were enrolled. Sixty-five single-nucleotide polymorphisms in 26 genes involved in the glycolytic pathway were evaluated. The associations of the variants with the chemotherapy response and overall survival (OS) were analyzed. Results: Among the 65 variants investigated, PFKL rs2073436C>G and GPI rs7248411C>G significantly correlated with clinical outcomes after chemotherapy in multivariate analyses. PFKL rs2073436C>G was significantly associated with both a worse response to chemotherapy (adjusted odds ratio [aOR] = 0.64, 95% CI = 0.45–0.90, p = 0.01) and a worse OS (adjusted hazard ratio [aHR] = 1.35, 95% CI = 1.14–1.61, p = 0.001). GPI rs7248411C>G was significantly associated with both a better chemotherapy response (aOR = 1.58, 95% CI = 1.07–2.23, p = 0.02) and a better OS (aHR = 0.80, 95% CI = 0.66–0.98, p = 0.03). When stratified by tumor histology, PFKL rs2073436C>G was significantly associated with OS only in squamous cell carcinoma, whereas GPI rs7248411C>G exhibited a significant association with the chemotherapy response and OS only in adenocarcinoma. Conclusion: This result suggests that the PFKL rs2073436C>G and GPI rs7248411C>G are useful for predicting the clinical outcome of first-line paclitaxel-cisplatin chemotherapy in NSCLC.

We evaluated the association between genetic variants in the Notch pathway and survival outcomes of patients with surgically resected NSCLC. 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. 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. These results suggest that DTX1 rs1732786 is a potential prognostic factor that may have clinical utility in the management of early stage NSCLC.

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 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 (P trend = 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 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).

Background MicroRNAs (miRNAs) have a key role in carcinogenesis through negative regulation of their target genes. Therefore, genetic variations in miRNAs or their target sites may affect miRNA–mRNA interactions, thereby result in altered expression of target genes. This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) located in the miRNA target sites (poly-miRTSs) and survival of patients with early-stage non-small-cell lung cancer (NSCLC). Methods Using public SNP database and miRNA target sites prediction program, 354 poly-miRTSs were selected for genotyping. Among these, 154 SNPs applicable to Sequenom's MassARRAY platform were investigated in 357 patients. A replication study was carried out on an independent patient population (n = 479). Renilla luciferase assay and reverse transcription-polymerase chain reaction were conducted to examine functional relevance of potentially functional poly-miRTSs. Results Of the 154 SNPs analyzed in a discovery set, 14 SNPs were significantly associated with survival outcomes. Among these, KRT81 rs3660G>C was found to be associated with survival outcomes in the validation cohort. In the combined analysis, patients with the rs3660 GC + CC genotype had a significantly better overall survival compared with those with GG genotype [adjusted hazard ratio (aHR) for OS, 0.65; 95% confidence interval (CI) 0.50–0.85; P = 0.001]. An increased expression of the reporter gene for the C allele of rs3660 compared with the G allele was observed by luciferase assay. Consistently, the C allele was associated with higher relative expression level of KRT81 in tumor tissues. Conclusion The rs3660G>C affects KRT81 expression and thus influences survival in early-stage NSCLC. The analysis of the rs3660G>C polymorphism may be useful to identify patients at high risk of a poor disease outcome.

Background We conducted this study to identify genetic variants in cancer-related pathway genes which can predict prognosis of NSCLC patients after surgery, using a comprehensive list of regulatory single nucleotide polymorphisms (SNPs) prioritized by RegulomeDB. Method A total of 509 potentially functional SNPs in cancer-related pathway genes selected from RegulomeDB were evaluated. These SNPs were analyzed in a discovery set (n = 354), and a replication study was performed in an independent set (n = 772). The association of the SNPs with overall survival (OS) and disease-free survival (DFS) were analyzed. Results In the discovery set, 76 SNPs were significantly associated with OS or DFS. Among the 76 SNPs, the association was consistently observed for 5 SNPs (ERCC1 rs2298881C > A, BRCA2 rs3092989G > A, NELFE rs440454C > T, PPP2R4 rs2541164G > A, and LTBP4 rs3786527G > A) in the validation set. In combined analysis, ERCC1 rs2298881C > A, BRCA2 rs3092989, NELFE rs440454C > T, and PPP2R4 rs2541164G > A were significantly associated with OS and DFS (adjusted HR ·aHR· for OS = 1.46, 0.62, 078, and 0.76, respectively; P = 0.003, 0.002, 0.007, and 0.003 respectively; and aHR for DFS = 1.27, 0.69, 0.86, and 0.82, respectively; P = 0.02, 0.002, 0.03, and 0.008, respectively). The LTBP4 rs3786527G > A was significantly associated with better OS (aHR = 0.75; P = 0.003). Conclusion Our results suggest that five SNPs in the cancer-related pathway genes may be useful for the prediction of the prognosis in patients with surgically resected NSCLC.

Phase development, sintering behaviors and dielectric characteristics of the composites between tungsten bronze structured Ba2NaNb 5 O 15 (BNN) and perovskite structured Pb(Mg 1/3 Nb 2/3 )O 3 (PMN) were examined as a function of molar ratio x in (1− x) BNN-xPMN. The lattice constant of BNN and PMN continuously changed throughout the entire composition change, which signifies that BNN and PMN have a wide range of solid solution with each other. The Curie temperature (T C ) and the maximum dielectric constant of BNN decreased as the content of PMN increased. Besides, when BNN is added to PMN, the T C also decreased and more dispersive dielectric relaxation was observed due to the incorporation of Na in PMN. The pyrochlore phase was formed in PMN rich compositions, which deteriorated the dielectric characteristics.

Vascular endothelial growth factor (VEGF) contributes to tumor angiogenesis. The role of VEGF single nucleotide polymorphisms (SNPs) in lung cancer susceptibility and its prognosis remains inconclusive and controversial. This study was performed to investigate whether VEGF polymorphisms affect survival outcomes of patients with early stage non-small cell lung cancer (NSCLC) after surgery. Three potentially functional VEGF SNPs (rs833061T>C, rs2010963G>C, and rs3025039C>T) were genotyped. A total of 782 NSCLC patients who were treated with surgical resection were enrolled. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. In overall population, none of the three polymorphisms were significantly associated with OS or DFS. However, when the patients were stratified by tumor histology, squamous cell carcinoma (SCC) and adenocarcinoma (AC) had significantly different OS (Adjusted hazard ratio [aHR] = 0.76, 95% CI = 0.56–1.03 in SCC; aHR = 1.33, 95% CI = 0.98–1.82 in AC; P for heterogeneity = 0.01) and DFS (aHR = 0.75, 95% CI = 0.58–0.97 in SCC; aHR = 1.26, 95% CI = 1.00–1.60 in AC; P for heterogeneity = 0.004) according to the rs833061T>C genotypes. Our results suggest that the prognostic role of VEGF rs833061T>C may differ depending on tumor histology., Graphical Abstract

Sudden sensorineural hearing loss that presents as the initial sign of haematological disease is very rare. Chronic myelogenous leukaemia has been implicated as a causative factor of sudden sensorineural hearing loss.A 49-year-old male presented with unilateral sudden sensorineural hearing loss. The patient was found to have chronic myelogenous leukaemia during a work-up for his hearing loss. We present a case of a chronic myelogenous leukaemia patient whose first manifestation was sudden sensorineural hearing loss. We presume that cochlear vessel occlusion as a result of elevated blood viscosity was responsible for this patient’s hearing loss. Early onset of sudden deafness in a chronic myelogenous leukaemia patient may be due to the hyperviscosity syndrome and it may be possible to reverse hearing loss through early leukapheresis.

A battery protection circuit is presented. The circuit is composed of charge/discharge control IC and power MOSFET. Simulation was performed with 0.5 /spl mu/m BCD technology and the RDS(ON) of the power MOSFET is 38 m/spl Omega/. The circuit reduces loss by RDS(ON) resistance more than the previous circuit. And it improves efficiency of the battery pack. Power dissipation of the power MOSFET is about 68 mW, when the current of the MOSFET is 1.3 A.

Aim: This study was performed to evaluate the prognostic relevance of PET parameters measured by F-18 FDG PET/CT in invasive ductal breast cancer (IDC) patients with distant metastasis at initial diagnosis. Methods: Forty female IDC patients with distant metastasis at initial diagnosis that underwent pretreatment F-18 FDG PET/CT were enrolled. Clinicopathologic parameters [age, TNM stage, location of metastatic lesion, estrogen receptor (ER) status, progesterone receptor (PR) status, human epidermal growth factor receptor2 (HER2) status] and metabolic PET parameters [SUVmax of the primary tumor (pSUVmax), SUVmax of axillary lymph node (nSUVmax), SUVmax of whole malignant lesions (wSUVmax), whole-body metabolic tumor volume (WBMTV), and whole-body total lesion glycolysis (WBTLG)] were analyzed with respect to the prediction of overall survival (OS). Univariate and multivariate analyses were performed to assess the prognostic significances of parameters using Kaplan-Meier and Cox proportional hazards models. Results: Twenty of the 40 patients (50 %) died during follow-up (mean, 34.7 months; range, 0.8–71.4 months). Non-survivors had a significantly higher mean WBMTV than survivors (444.7 ± 695.0 cm3, vs. 88.0 ± 95.4 cm3, p = 0.0287). Receiver-operating-characteristic analysis showed that a WBMTV of 167.8 cm3 (sensitivity, 50.0 %; specificity, 90.0 %; area under the curve, 0.670) was an optimal cutoff for predicting OS. T stage, location of metastatic lesion, ER status, PR status, wSUVmax, WBMTV, and WBTLG were found to be prognostic factors of OS by univariate analysis, but age, N stage, pSUVmax, nSUVmax, and HER2 status were not. Multivariate analysis revealed only WBMTV independently predicted OS (HR, 4.70; 95 % CI, 1.33–16.56; p = 0.0165). Conclusions: WBMTV on pretreatment F-18 FDG PET/CT was found to be an independent prognostic factor of OS in invasive ductal breast cancer patients with distant metastasis at initial diagnosis. Disclosure: All authors have declared no conflicts of interest.