Publications by authors named "Hyo-Gyoung Kang"

51 Publications

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

Oncology 2021 Feb 24:1-9. Epub 2021 Feb 24.

Department of Biochemistry, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

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.
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http://dx.doi.org/10.1159/000514131DOI Listing
February 2021

Impact of immune checkpoint gene CD155 Ala67Thr and CD226 Gly307Ser polymorphisms on small cell lung cancer clinical outcome.

Sci Rep 2021 Jan 19;11(1):1794. Epub 2021 Jan 19.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, 41944, Republic of Korea.

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, 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.
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http://dx.doi.org/10.1038/s41598-021-81260-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815735PMC
January 2021

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

Oncology 2020 13;98(12):897-904. Epub 2020 Aug 13.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

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.
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http://dx.doi.org/10.1159/000509658DOI Listing
December 2020

Effect of genetic variation in Notch regulator DTX1 on SCLC prognosis compared with the effect on NSCLC prongosis.

Thorac Cancer 2020 09 22;11(9):2698-2703. Epub 2020 Jul 22.

Department of Internal Medicine, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea.

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 ; 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 ). 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).
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http://dx.doi.org/10.1111/1759-7714.13566DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471053PMC
September 2020

Polymorphisms in Glycolysis-Related Genes Are Associated with Clinical Outcomes of Paclitaxel-Cisplatin Chemotherapy in Non-Small Cell Lung Cancer.

Oncology 2020 6;98(7):468-477. Epub 2020 Apr 6.

Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea,

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.
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http://dx.doi.org/10.1159/000504175DOI Listing
July 2020

The effect of susceptibility variants, identified in never-smoking female lung cancer cases, on male smokers.

Korean J Intern Med 2020 07 30;35(4):929-935. Epub 2019 Dec 30.

Department of Internal Medicine, Kyungpook National University Hospital, Daegu, Korea.

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.
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http://dx.doi.org/10.3904/kjim.2018.417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7373985PMC
July 2020

Polymorphism in ASCL1 target gene DDC is associated with clinical outcomes of small cell lung cancer patients.

Thorac Cancer 2020 01 5;11(1):19-28. Epub 2019 Nov 5.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

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.
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http://dx.doi.org/10.1111/1759-7714.13212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938757PMC
January 2020

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

Ann Surg Oncol 2019 Oct 16;26(11):3756-3764. Epub 2019 Jul 16.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea.

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 (P = 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.
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http://dx.doi.org/10.1245/s10434-019-07614-2DOI Listing
October 2019

Glucose transporter 3 gene variant is associated with survival outcome of patients with non-small cell lung cancer after surgical resection.

Gene 2019 Jun 4;703:58-64. Epub 2019 Apr 4.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Lung Cancer Center, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea; Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

This study was conducted to explore whether polymorphisms of glucose transporter 3 (GLUT3) gene affect the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Four single nucleotide polymorphisms (SNPs) in GLUT3 were investigated in a total of 782 patients with NSCLC who underwent curative surgery. The association of the SNPs with overall survival (OS) and disease free survival (DFS) was analyzed. Among the four SNPs investigated, GLUT3 rs7309332C>T was significantly associated with OS and DFS in multivariate analyses. The SNP was associated with significantly worse OS (adjusted hazard ratio [aHR] = 1.62, 95% confidence interval [CI] = 1.04-2.53, P = 0.03, under recessive model), and worse DFS (aHR = 1.64, 95% CI = 1.18-2.29, P = 0.003, under recessive model). When stratified by tumor histology, the association between the GLUT3 rs7309332C>T and OS/DFS was not limited to either squamous cell carcinoma (SCC) or adenocarcinoma (AC), although the significant association remained only in AC for OS (P = 0.40 for SCC and P = 0.04 for OS) and only in SCC for DFS (P = 0.03 for SCC and P = 0.08 for OS). When AC patients were stratified according to EGFR mutation status, the SNP was significantly associated with DFS in patients with EGFR mutant tumors (aHR = 2.47, 95% CI = 1.15-5.30, P = 0.02, under recessive model), but not in those with EGFR wild-type tumors. This study suggests that genetic variation in GLUT3 may be useful in predicting survival of patients with early stage NSCLC.
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http://dx.doi.org/10.1016/j.gene.2019.04.013DOI Listing
June 2019

TSC2 genetic variant and prognosis in non-small cell lung cancer after curative surgery.

Thorac Cancer 2019 02 26;10(2):335-340. Epub 2018 Dec 26.

Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea.

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.
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http://dx.doi.org/10.1111/1759-7714.12951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360237PMC
February 2019

An expression quantitative trait locus variant for LKB1 gene predicts the clinical outcomes of chemotherapy in patients with non-small cell lung cancer.

Cancer Genet 2018 12 16;228-229:73-82. Epub 2018 Oct 16.

Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Lung Cancer Center, Kyungpook National University Chilgok Hospital, Daegu, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

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.
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http://dx.doi.org/10.1016/j.cancergen.2018.10.002DOI Listing
December 2018

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

Cancer Sci 2018 Dec 7;109(12):3902-3909. Epub 2018 Nov 7.

Department of Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea.

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 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 = 0.03) and was significantly higher in tumor than in non-malignant lung tissues (P = 1 × 10 ). 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).
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http://dx.doi.org/10.1111/cas.13814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6272084PMC
December 2018

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

Ann Surg Oncol 2018 Oct 30;25(11):3396-3403. Epub 2018 Jul 30.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

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).

Conclusions: This study suggests that genetic variation in GLUT1 may be useful in predicting survival of patients with early stage NSCLC.
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http://dx.doi.org/10.1245/s10434-018-6677-1DOI Listing
October 2018

Intronic variant of EGFR is associated with GBAS expression and survival outcome of early-stage non-small cell lung cancer.

Thorac Cancer 2018 08 28;9(8):916-923. Epub 2018 May 28.

Department of Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Korea.

Background: Genome-wide association studies have indicated that most of the currently identified disease and trait-associated single nucleotide polymorphisms (SNPs) are intronic or intergenic. RegulomeDB is a recently developed database that provides functional annotations for regulatory features of SNPs located in non-coding regions. We evaluated the potential regulatory SNPs in the EGFR gene region using RegulomeDB and their associations with prognosis after surgery in non-small cell lung cancer (NSCLC) patients.

Methods: A total of 698 patients with surgically resected NSCLC were enrolled and seven SNPs were selected based on the RegulomeDB database. All SNPs were genotyped using SEQUENOM MassARRAY iPLEX assay.

Results: Among the seven SNPs evaluated, rs9642391 (EGFR ivs19+2851C>G) was significantly associated with survival outcome (adjusted hazard ratio [HR] for overall survival = 0.70, 95% confidence interval [CI] 0.56-0.87, P = 0.001; adjusted HR for disease-free survival = 0.82, 95% CI 0.70-0.97, P = 0.02; under a codominant model). According to RegulomeDB, rs9642391C>G, which is located in intron 19 of EGFR, was predicted to influence the expression of GBAS but not EGFR. As predicted, rs9642391C>G was associated with GBAS (P = 0.024) but not EGFR messenger RNA expression in tumor tissues.

Conclusion: In conclusion, our study provides evidence that rs9642391C>G in the intron of EGFR is associated with GBAS expression and survival outcomes of patients with surgically resected early-stage NSCLC.
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http://dx.doi.org/10.1111/1759-7714.12757DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6068432PMC
August 2018

Regulatory variants in cancer-related pathway genes predict survival of patients with surgically resected non-small cell lung cancer.

Gene 2018 Mar 29;646:56-63. Epub 2017 Dec 29.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea; Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. Electronic address:

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.
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http://dx.doi.org/10.1016/j.gene.2017.12.055DOI Listing
March 2018

Polymorphisms in mitotic checkpoint-related genes can influence survival outcomes of early-stage non-small cell lung cancer.

Oncotarget 2017 Sep 27;8(37):61777-61785. Epub 2017 Jun 27.

Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

This study was conducted to investigate the association between variants in mitotic checkpoint-related genes and clinical outcomes of non-small cell lung cancer (NSCLC). A total of 766 patients with NSCLC who underwent curative surgery were enrolled. Among the 73 variants evaluated, 4 variants were related with survival outcomes. rs7897156C>T was associated with worse overall survival under a recessive model (adjusted hazard ratio = 1.58, 95% confidence interval = 1.07-2.33, = 0.02). rs1059476G>A was associated with better overall survival under a recessive model (adjusted hazard ratio = 0.64, 95% confidence interval = 0.41-0.99, = 0.05). rs1895320T>C and rs1374297C>G were associated with worse disease-free survival. In the functional study, relative luciferase activity was higher at the rs7897156T allele compared to that at the C allele. Western blot showed that the phosphorylation of AKT and mTOR in the variant-type (M) was significantly lower than in the wild-type (T). We found that 4 variants of mitotic checkpoint-related genes were associated with survival outcomes in patients with surgically resected NSCLC. Particularly, our results suggest that rs7897156C>T and rs1059476G>A are functional variants.
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http://dx.doi.org/10.18632/oncotarget.18693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5617463PMC
September 2017

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

Ann Surg Oncol 2017 Oct 1;24(11):3386-3395. Epub 2017 Aug 1.

Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.

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). 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.
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http://dx.doi.org/10.1245/s10434-017-6002-4DOI Listing
October 2017

Effects of polymorphisms identified in genome-wide association studies of never-smoking females on the prognosis of non-small cell lung cancer.

Cancer Genet 2017 04 20;212-213:8-12. Epub 2017 Mar 20.

Departments of Internal Medicine, Kyungpook National University School of Medicine, Daegu, South Korea; Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu, South Korea. Electronic address:

A number of genome-wide association studies have reported several variants that influence the risk of lung cancer in never-smoking females. We evaluated the impact of these variants on survival outcome in never-smoking females with non-small cell lung cancer (NSCLC). In total, 510 never-smoking females with NSCLC who underwent curative surgery were enrolled. Eleven variants associated with lung cancer susceptibility in never-smoking females were genotyped and their associations with survival outcome were analyzed. Among these 11 variants, TP63 rs7631358 and CSF1R rs10079250 affected survival outcomes. TP63 rs7631358 G > A was associated with a relatively worse overall survival (under a dominant model; hazard ratio = 2.31, 95% confidence interval = 1.18-4.52, P = 0.01). CSF1R rs10079250 A > G was associated with a relatively better disease-free survival (under a codominant model; hazard ratio = 0.70, 95% confidence interval = 0.53-0.93, P = 0.01). These results suggest that TP63 rs7631358 G > A and CSF1R rs10079250 A > G may affect the prognosis of NSCLC in never-smoking females, as well as the risk of lung cancer.
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http://dx.doi.org/10.1016/j.cancergen.2017.03.003DOI Listing
April 2017

Development of a prognosis-prediction model incorporating genetic polymorphism with pathologic stage in stage I non-small cell lung cancer: A multicenter study.

Thorac Cancer 2017 05 31;8(3):251-259. Epub 2017 Mar 31.

Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea.

Background: This multicenter study was performed to develop a prognosis-prediction model incorporating genetic polymorphism with pathologic stage for surgically treated non-small cell lung cancer (NSCLC) patients.

Methods: A replication study including 720 patients and a panel of eight single nucleotide polymorphisms (SNPs), which predicted the prognosis of surgically treated NSCLC in our previous study, was conducted. Using the combined cohort of current and previous studies including 1534 patients, a nomogram for predicting overall survival was made using Cox proportional hazards regression.

Results: Among the eight SNPs, C3 rs2287845, GNB2L1 (alias RACK1), and rs3756585 were significantly associated with overall survival. A nomogram was constructed based on pathologic stage and the genotypes of the two SNPs, and the risk score was calculated for each patient in the combined cohort. Using the prognosis-prediction model, we categorized patients into low, intermediate, and high-risk groups, which had greater accuracy in predictive ability (log-rank statistics = 54.66) than the conventional tumor node metastasis staging (log-rank statistics = 39.56). Next, we generated a prognosis-prediction model for stage I to identify a subgroup of potential candidates for adjuvant chemotherapy. Notably, 97 out of 499 stage IB patients were classified as high-risk patients with a similar prognosis to stage II patients, suggesting the benefit of adjuvant chemotherapy.

Conclusions: This prognosis-prediction model incorporating genetic polymorphism with pathologic stage may lead to more precise prognostication in surgically resected NSCLC patients. In particular, this model may be useful in selecting a subgroup of stage IB patients who may benefit from adjuvant chemotherapy.
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http://dx.doi.org/10.1111/1759-7714.12434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5415483PMC
May 2017

Functional polymorphisms in PD-L1 gene are associated with the prognosis of patients with early stage non-small cell lung cancer.

Gene 2017 Jan 10;599:28-35. Epub 2016 Nov 10.

Department of Internal Medicine, Kyungpook National University School of Medicine, Daegu 700-842, Republic of Korea; Department of Biochemistry and Cell Biology, Kyungpook National University School of Medicine, Daegu 700-842, Republic of Korea; Cell and Matrix Research Institute, Kyungpook National University School of Medicine, Daegu 700-842, Republic of Korea; Lung Cancer Center, Kyungpook National University Medical Center, Daegu 702-201, Republic of Korea; BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu 700-842, Republic of Korea. Electronic address:

Introduction: This study was conducted to investigate whether polymorphisms of genes involved in immune checkpoints can predict the prognosis of patients with early stage non-small cell lung cancer (NSCLC) after surgical resection.

Materials And Methods: Twelve single nucleotide polymorphisms (SNPs) of PD-1, PD-L1, and CTLA-4 genes were selected and genotyped. A total of 354 patients with early stage NSCLC who underwent curative surgical resection were enrolled. The association of the SNPs with overall survival (OS) was analyzed.

Results: Among the 12 SNPs investigated, PD-L1 rs4143815C>G, rs822336G>C, and rs822337T>A were significantly associated with worse survival outcomes in multivariate analyses. When the three SNPs were combined, OS decreased in a dose-dependent manner as the number of bad genotypes increased (P=0.0003). In the luciferase assay, rs4143815 G allele exhibited a decreased transcription activity compared with C allele (P=0.001), and the rs822336C-rs822337A haplotype had a decreased promoter activity compared with the rs822336G-rs822337T haplotype (P=0.004). Patients with higher expression of PD-L1 mRNA had a better survival compared with lower expression (P=0.03).

Conclusions: PD-L1 polymorphisms may be useful for the prediction of prognosis in patients with surgically resected NSCLC. Further studies are needed to confirm our findings and to understand the role of PD-L1 in the antitumor immunity and prognosis in NSCLC.
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http://dx.doi.org/10.1016/j.gene.2016.11.007DOI Listing
January 2017

Genetic polymorphisms in glycolytic pathway are associated with the prognosis of patients with early stage non-small cell lung cancer.

Sci Rep 2016 10 21;6:35603. Epub 2016 Oct 21.

Lung Cancer Center, Kyungpook National University Medical Center, Daegu 41404, Republic of Korea.

This study was conducted to investigate whether polymorphisms of genes involved in glycolysis are associated with the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Forty-four single nucleotide polymorphisms (SNPs) of 17 genes in glycolytic pathway were investigated in a total of 782 patients with NSCLC who underwent curative surgical resection. The association of the SNPs with overall survival (OS) and disease free survival (DFS) were analyzed. Among the 44 SNPs investigated, four SNPs (ENO1 rs2274971A > G, PFKM rs11168417C > T, PFKP rs1132173C > T, PDK2 rs3785921G > A) were significantly associated with survival outcomes in multivariate analyses. When stratified by tumor histology, three SNPs (ENO1 rs2274971A > G, PFKM rs11168417C > T, and PDK2 rs3785921G > A) were significantly associated with OS and/or DFS only in squamous cell carcinoma, whereas PFKP rs1132173C > T exhibited a significant association with survival outcomes only in adenocarcinoma. When the four SNPs were combined, OS and DFS decreased as the number of bad genotypes increased (Ptrend = 8 × 10 and 3 × 10, respectively). Promoter assays showed that ENO1 rs2274971G allele had significantly higher promoter activity compared to the rs2274971A allele. The four SNPs, especially ENO1 rs2274971A > G, may be useful for the prediction of prognosis in patients with surgically resected NSCLC.
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http://dx.doi.org/10.1038/srep35603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5073284PMC
October 2016

The Different Effect of VEGF Polymorphisms on the Prognosis of Non-Small Cell Lung Cancer according to Tumor Histology.

J Korean Med Sci 2016 Nov;31(11):1735-1741

Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.

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.
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http://dx.doi.org/10.3346/jkms.2016.31.11.1735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5056204PMC
November 2016

Polymorphisms in cancer-related pathway genes and lung cancer.

Eur Respir J 2016 10 1;48(4):1184-1191. Epub 2016 Sep 1.

Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Korea Dept of Internal Medicine, Kyungpook National University, Daegu, Korea Dept of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Korea

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, 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 (p=0.03).These results suggest that the three SNPs, particularly CIR1 rs13009079T>C, may play a role in the pathogenesis of lung cancer.
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http://dx.doi.org/10.1183/13993003.02040-2015DOI Listing
October 2016

PD-L1 polymorphism can predict clinical outcomes of non-small cell lung cancer patients treated with first-line paclitaxel-cisplatin chemotherapy.

Sci Rep 2016 05 16;6:25952. Epub 2016 May 16.

Lung Cancer Center, Kyungpook National University Medical Center, Daegu 702-201, Republic of Korea.

This study was conducted to investigate whether polymorphisms of genes involved in immune checkpoints can predict the clinical outcomes of patients with advanced stage non-small cell lung cancer (NSCLC) after 1st line paclitaxel-cisplatin chemotherapy. A total of 379 NSCLC patients were enrolled. Twelve single nucleotide polymorphisms (SNPs) of PD-1, PD-L1, and CTLA-4 genes were selected and genotyped. The associations of SNPs with chemotherapy response and overall survival (OS) were analyzed. Among the 12 SNPs investigated, PD-L1 rs2297136T > C and rs4143815C > G were significantly associated with clinical outcomes after chemotherapy. The rs2297136T > C was significantly associated with both better chemotherapy response and better OS, and the rs4143815C > G had a significantly better response to chemotherapy. Consistent with the individual genotype analyses, rs2297136C-rs4143815G haplotype (ht4) carrying variant alleles at both loci was significantly associated with better chemotherapy response and OS compared with combined other haplotypes. Patients with at least one ht4 had significantly better chemotherapy response and OS compared to those without ht4. PD-L1 rs2297136T > C and rs4143815C > G polymorphisms may be useful for the prediction of clinical outcome of 1(st) line paclitaxel-cisplatin chemotherapy in NSCLC. Further studies are needed to confirm our findings and to understand the role of PD-L1 in the chemotherapy outcome of NSCLC patients.
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http://dx.doi.org/10.1038/srep25952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4867646PMC
May 2016

A Panel of Genetic Polymorphism for the Prediction of Prognosis in Patients with Early Stage Non-Small Cell Lung Cancer after Surgical Resection.

PLoS One 2015 13;10(10):e0140216. Epub 2015 Oct 13.

Departments of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Departments of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Republic of Korea; Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.

Background: This study was conducted to investigate whether a panel of eight genetic polymorphisms can predict the prognosis of patients with early stage non-small cell lung cancer (NSCLC) after surgical resection.

Materials And Methods: We selected eight single nucleotide polymorphisms (SNPs) which have been associated with the prognosis of lung cancer patients after surgery in our previous studies. A total of 814 patients with early stage NSCLC who underwent curative surgical resection were enrolled. The association of the eight SNPs with overall survival (OS) and disease-free survival (DFS) was analyzed.

Results: The eight SNPs (CD3EAP rs967591, TNFRSF10B rs1047266, AKT1 rs3803300, C3 rs2287845, HOMER2 rs1256428, GNB2L1 rs3756585, ADAMTSL3 rs11259927, and CD3D rs3181259) were significantly associated with OS and/or DFS. Combining those eight SNPs, we designed a prognostic index to predict the prognosis of patients. According to relative risk of death, a score value was assigned to each genotype of the SNPs. A worse prognosis corresponded to a higher score value, and the sum of score values of eight SNPs defined the prognostic index of a patient. When we categorized the patients into two groups based on the prognostic index, high risk group was significantly associated with worse OS and DFS compared to low risk group (aHR for OS = 2.21, 95% CI = 1.69-2.88, P = 8.0 x 10-9, and aHR for DFS = 1.58, 95% CI = 1.29-1.94, P = 1.0 x 10-5).

Conclusions: Prognostic index using eight genetic polymorphisms may be useful for the prognostication of patients with surgically resected NSCLC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0140216PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4603900PMC
June 2016

Functional intronic ERCC1 polymorphism from regulomeDB can predict survival in lung cancer after surgery.

Oncotarget 2015 Sep;6(27):24522-32

Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea.

We searched for potential regulatory single nucleotide polymorphisms (SNPs) in excision repair cross-complementing group 1 (ERCC1) using RegulomeDB, a database integrating information from the Encyclopedia of DNA Elements (ENCODE) project, and investigated their association with survival after surgery in non-small cell lung cancer (NSCLC). Among 364 SNPs found within ERCC1 region using RegulomeDB, four top priority SNPs (rs2298881C>A, rs1049739A>G, rs10415949A>G and rs6509214G>T) were selected for this study. The four SNPs were investigated in 316 patients. A replication study was performed (n = 579). Of the four SNPs analyzed in the discovery set, rs2298881C>A and rs6509214G>T were significantly associated with survival outcomes. The association was consistently observed only for rs2298881C>A in the validation cohort. In combined analysis, rs2298881C>A was significantly associated with worse overall survival and disease-free survival (P = 0.0002 and 0.02, respectively). A decreased reporter gene expression for rs2298881 A allele was observed compared with C allele by luciferase assay (P = 0.02). ERCC1 rs2298881C>A, an intronic SNP, is the first genetic polymorphism with functional evidence of regulating its expression, and the SNP is associated with prognosis of NSCLC. Our result supports the role of RegulomeDB as a comprehensive source of prioritized candidate SNPs for genetic association studies.
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http://dx.doi.org/10.18632/oncotarget.4083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4695203PMC
September 2015

RACK1 is a candidate gene associated with the prognosis of patients with early stage non-small cell lung cancer.

Oncotarget 2015 Feb;6(6):4451-66

Departments of Biochemistry and Cell Biology, Kyungpook National University, Daegu, Republic of Korea.

Background: This study was conducted to identify genetic polymorphisms associated with the prognosis of patients with early stage NSCLC.

Materials And Methods: We genotyped 1,969 potentially functional single nucleotide polymorphisms (SNPs) of 1,151 genes involved in carcinogenesis in 166 NSCLC patients who underwent curative surgery, using the Affymetrix custom-made GeneChip. A replication study was performed in an independent cohort of 626 patients.

Results: Fifty six SNPs which were associated with both overall survival (OS) and disease-free survival (DFS) with log-rank P values < 0.05 in discovery set were selected for validation. Among those, five SNPs (RACK1 rs1279736C>A and rs3756585T>G, C3 rs2287845T>C, PCAF rs17006625A>G, and PCM1 rs17691523C>G) were found to be significantly associated with survival in the same direction as the discovery set. In combined analysis, the rs1279736C>A and rs3756585T>G were most significantly associated with OS and DFS in multivariate analysis (P for OS = 4 × 10⁻⁵ and 7 × 10⁻⁵, respectively; and P for DFS = 0.003, both; under codominant model). In vitro promoter assay and electrophoretic mobility shift assay revealed that the rs3756585 T-to-G change increased promoter activity and transcription factor binding of RACK1.

Conclusions: We identified five SNPs, especially RACK1 rs3756585T>G, as markers for prognosis of patients with surgically resected NSCLC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4414203PMC
http://dx.doi.org/10.18632/oncotarget.2865DOI Listing
February 2015

A functional polymorphism in CSF1R gene is a novel susceptibility marker for lung cancer among never-smoking females.

J Thorac Oncol 2014 Nov;9(11):1647-55

*Department of Biochemistry and Cell Biology and †Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea; ‡Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Korea; §Biostatistics Center, School of Medicine, Kyungpook National University, Daegu, Korea; ‖D&P Biotech, Inc., Daegu, Korea; ¶Department of Thoracic and Cardiovascular Surgery, Clinical Research Institute, Seoul National University Hospital, Seoul, Korea; #Genomic Medicine Institute, Cancer Research Institute, Seoul National University, Seoul, Korea; **Department of Environmental Health, Graduate School of Public Health, Seoul National University, Seoul, Korea; ††Department of Preventive Medicine, Seoul National University School of Medicine, Seoul, Korea; ‡‡Division of Oncology/Hematology, Department of Internal Medicine, College of Medicine, Korea University, Seoul, Korea; and §§Cancer Research Institute, Korea University, Seoul, Korea.

Introduction: It has been estimated that the proportion of never-smokers among females with lung cancer is 53% worldwide and 75% in Korea. We conducted a two-stage study to identify genetic factors responsible for lung cancer susceptibility in female never-smokers.

Materials And Methods: In a discovery set, 1969 potentially functional single nucleotide polymorphisms (SNPs) of 1151 genes, which were related to cancer development and progression, were evaluated using the Affymetrix custom-made GeneChip in 181 female never-smokers with lung cancer and 179 controls. A replication study was performed on an independent cohort of 596 cases and 1194 healthy controls.

Results: Sixteen SNPs with p < 0.05 for genotype distribution in the discovery set were enrolled in the replication study. Among 16 SNPs, three SNPs (colony-stimulating factor 1 receptor [CSF1R] rs10079250A>G, tumor protein p63 [TP63] rs7631358G>A, and corepressor interacting with RBPJ 1 [CIR1] rs13009079T>C) were found to be significantly associated with lung cancer in the same direction as the discovery set. Homology-based model for CSF1R indicated that the rs10079250A>G leads to increased positive charge of CSF-binding region of CSF1R, thereby increasing the chance of binding between CSF and CSF1R. In addition, this SNP was found to increase the phosphorylation of a mitogen-activated protein kinase, JNK.

Conclusions: Our results suggest that the three SNPs, particularly CSF1R rs10079250, may contribute to lung cancer susceptibility in never-smoking females.
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http://dx.doi.org/10.1097/JTO.0000000000000310DOI Listing
November 2014

Polymorphisms in DNA repair and apoptosis-related genes and clinical outcomes of patients with non-small cell lung cancer treated with first-line paclitaxel-cisplatin chemotherapy.

Lung Cancer 2013 Nov 8;82(2):330-9. Epub 2013 Aug 8.

Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, South Korea.

This study was conducted to analyze a comprehensive panel of single nucleotide polymorphisms (SNPs) in genes in DNA repair and apoptosis pathways and determine the relationship between polymorphisms and treatment outcomes of patients with non-small cell lung cancer (NSCLC) treated with first-line paclitaxel-cisplatin chemotherapy. Three hundred eighty two patients with NSCLC were enrolled. Seventy-four SNPs in 48 genes (42 SNPs in 27 DNA repair pathway genes and 32 SNPs in 21 apoptotic pathway genes) were genotyped and their associations with chemotherapy response and overall survival (OS) were analyzed. Among SNPs in DNA repair genes, BRCA1 rs799917 was significantly associated with both chemotherapy response and OS. XRCC1 rs25487 exhibited a significant association with chemotherapy response and ERCC2 rs1052555 with OS. Four SNPs in apoptotic genes (TNFRSF1B rs1061624, BCL2 rs2279115, BIRC5 rs9904341, and CASP8 rs3769818) were significantly associated with OS, but not with response to chemotherapy. When the six SNPs which were associated with OS in individual analysis were combined, OS decreased as the number of bad genotypes increased (P(trend) = 2 × 10(-6)). Patients with 3, and 4-6 bad genotypes had significantly worse OS compared with those carrying 0-2 bad genotypes (adjusted hazard ratio [aHR] = 1.54, 95% CI = 1.14-2.08, P = 0.005; aHR = 2.10, 95% CI = 1.55-2.85, P = 2 × 10(-6), respectively). In conclusion, these findings suggest that the six SNPs identified, particularly their combined genotypes, could be used as biomarkers predicting chemotherapy response and survival of NSCLC patients treated with first-line paclitaxel-cisplatin chemotherapy.
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http://dx.doi.org/10.1016/j.lungcan.2013.07.024DOI Listing
November 2013

A functional variant at 19q13.3, rs967591G>A, is associated with shorter survival of early-stage lung cancer.

Clin Cancer Res 2013 Aug 17;19(15):4185-95. Epub 2013 Jun 17.

Lung Cancer Center, Kyungpook National University Medical Center, Daegu, Republic of Korea.

Purpose: This study was conducted to investigate the associations between single-nucleotide polymorphisms (SNP) in 19q13.3 and survival of patients with early-stage non-small cell lung cancer (NSCLC), and to define the causative functional SNP of the association.

Experimental Design: A two-stage study design was used to evaluate five SNPs in relation to survival outcomes in 328 patients and then to validate the results in an independent patient population (n = 483). Luciferase assay and real-time PCR were conducted to examine functional relevance of a potentially functional SNP.

Results: Of the five SNPs, three SNPs (rs105165C>T, rs967591G>A, and rs735482A>C) were significantly associated with survival outcomes in a stage I study. The rs967591A allele had significantly higher activity of the CD3EAP promoter compared with the rs967591G allele (P = 0.002), but the SNP did not have an effect on the activity of PPP1R13L promoter. The rs967591G>A was associated with the level of CD3EAP mRNA expression in lung tissues (P = 0.01). The rs967591G>A exhibited consistent associations in a stage II study. In combined analysis, the rs967591 AA genotype exhibited a worse overall survival (adjusted HR = 1.69; 95% confidence interval = 1.29-2.20; P = 0.0001).

Conclusion: The rs967591G>A affects CD3EAP expression and thus influences survival in early-stage NSCLC. The analysis of the rs967591G>A polymorphism can help identify patients at high risk of a poor disease outcome.
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http://dx.doi.org/10.1158/1078-0432.CCR-12-2792DOI Listing
August 2013