Publications by authors named "Jang Hyuck Lee"

18 Publications

  • Page 1 of 1

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

Authors:
Hyo-Gyoung Kang Ji Eun Park Shin Yup Lee Jin Eun Choi Sook Kyung Do Mi Jeong Hong Jang Hyuck Lee Ji Yun Jeong Young Woo Do Eung Bae Lee Kyung Min Shin Won Ki Lee Sun Ha Choi Yong Hoon Lee Hye Won Seo Seung Soo Yoo Jaehee Lee Seung Ick Cha Chang Ho Kim Sukki Cho Sanghoon Jheon Jae Yong Park

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.

Authors:
Jang Hyuck Lee Seung Soo Yoo Mi Jeong Hong Jin Eun Choi Soyoun Kim Hyo-Gyoung Kang Sook Kyung Do Ji Hyun Kim Sun Ah Baek Won Kee Lee Jae Do Yoo Sun Ha Choi Yong Hoon Lee Hyewon Seo Jaehee Lee Shin Yup Lee Seung Ick Cha Chang Ho Kim Jae Yong Park

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.

Authors:
Sook Kyung Do Sun Ha Choi Shin Yup Lee Jin Eun Choi Hyo-Gyoung Kang Mi Jeong Hong Ji Hyun Kim Sun Ah Baek Jang Hyuck Lee Won Kee Lee Young Woo Do Eung Bae Lee Kyung Min Shin Ji Yun Jeong Yong Hoon Lee Hyewon Seo Seung Soo Yoo Jaehee Lee Seung Ick Cha Chang Ho Kim Yangki Seok Sukki Cho Sanghoon Jheon Jae Yong Park

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

Expression of key regulatory genes in necroptosis and its effect on the prognosis in non-small cell lung cancer.

Authors:
Ji Eun Park Jang Hyuck Lee Shin Yup Lee Mi Jeong Hong Jin Eun Choi Sunji Park Ji Yun Jeong Eung Bae Lee Sun Ha Choi Yong Hoon Lee Hye Won Seo Seung Soo Yoo Jaehee Lee Seung Ick Cha Chang Ho Kim Jae Yong Park

J Cancer 2020 11;11(18):5503-5510. Epub 2020 Jul 11.

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

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. 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 , , and . Difference in disease free survival (DFS) was analyzed according to the expression levels of these molecules in tumor tissues. NSCLC tissues had significantly lower expression of , , and than normal tissues ( = 1 x 10, = 8 x 10, and = 4 x 10, respectively). In subgroup analysis, SCCs had significantly lower , , and expression ( = 5 x 10, = 3 x 10, = 1 x 10, respectively), and ACs had significantly lower and expression ( = 0.01 and = 6 x 10, respectively) than normal tissues. Low expression of , , and in tumors was associated with a worse DFS (HR = 1.71, = 0.01; HR = 1.53, = 0.04; and HR = 1.53, = 0.04, respectively) in a multivariate analysis. In SCC, none of the , , and expression was significantly associated with DFS. However, in AC, low expression of , , and was significantly associated with worse DFS (HR = 1.67, = 0.03; HR = 1.70, = 0.03; and HR = 1.81, = 0.02, respectively). Key regulatory genes in necroptosis, , , and , were downregulated in NSCLC, and their lower expression in NSCLC may be used to predict early recurrence after curative resection, especially in AC.
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http://dx.doi.org/10.7150/jca.46172DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391199PMC
July 2020

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

Authors:
Seung Soo Yoo Jang Hyuck Lee Mi Jeong Hong Jin Eun Choi Hyo-Gyoung Kang Sook Kyung Do Ji Hyun Kim Sun Ah Baek Sun Ha Choi Won Kee Lee Yong Hoon Lee Hyewon Seo Jaehee Lee Shin Yup Lee Seung Ick Cha Chang Ho Kim Jae Yong Park

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.

Authors:
Sun Ha Choi Cheng Cheng Jin Sook Kyung Do Shin Yup Lee Jin Eun Choi Hyo-Gyoung Kang Ji Hyun Kim Jang Hyuck Lee Mi Jeong Hong Won Kee Lee Ji Yun Jeong Kyung Min Shin Yong Hoon Lee Hyewon Seo Seung Soo Yoo Jaehee Lee Seung Ick Cha Chang Ho Kim Jae Yong Park

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.

Authors:
Seung Soo Yoo Hyo-Gyoung Kang Jin Eun Choi Mi Jeong Hong Sook Kyung Do Jang Hyuck Lee Won Kee Lee Shin Yup Lee Jaehee Lee Seung Ick Cha Chang Ho Kim Eung Bae Lee Jae Yong Park

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.

Authors:
Ji Hyun Kim Shin Yup Lee Jin Eun Choi Sook Kyung Do Jang Hyuck Lee Mi Jeong Hong Hyo-Gyoung Kang Won Kee Lee Kyung Min Shin Ji Yun Jeong Sun Ha Choi Yong Hoon Lee Hyewon Seo Seung Soo Yoo Jaehee Lee Seung Ick Cha Chang Ho Kim Jae Yong Park

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.

Authors:
Jang Hyuck Lee Kyung Min Shin Shin Yup Lee Mi Jeong Hong Jin Eun Choi Hyo-Gyoung Kang Sook Kyung Do Won Kee Lee Eung Bae Lee Yangki Seok Ji Yun Jeong Seung Soo Yoo Jaehee Lee Seung Ick Cha Chang Ho Kim Sukki Cho Sanghoon Jheon Young Chul Kim In Jae Oh Kook Joo Na Moon Soo Kim Jong Mog Lee Hee Chul Yang Chi Young Jung Chang Kwon Park Min Ki Lee Dong Kwan Kim Jae Yong Park

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

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

Authors:
Yong Hoon Lee Sook Kyung Do Shin Yup Lee Hyo-Gyoung Kang Jin Eun Choi Mi Jeong Hong Jang Hyuck Lee Eung Bae Lee Ji Yun Jeong Kyung Min Shin Won Kee Lee Yangki Seok Sukki Cho Seung Soo Yoo Jaehee Lee Seung Ick Cha Chang Ho Kim Sanghoon Jheon Jae Yong Park

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.

Authors:
Hyewon Seo Deuk Kju Jung Hyo-Gyoung Kang Ji Yun Jeong Shin Yup Lee Jin Eun Choi Mi Jeong Hong Sook Kyung Do Jang Hyuck Lee Won Kee Lee Kyung Min Shin Seung Soo Yoo Jaehee Lee Seung Ick Cha Chang Ho Kim Jae Yong Park

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.

Authors:
Mi Jeong Hong Seung Soo Yoo Jin Eun Choi Hyo-Gyoung Kang Sook Kyung Do Jang Hyuck Lee Won Kee Lee Jaehee Lee Shin Yup Lee Seung Ick Cha Chang Ho Kim Eung Bae Lee Sukki Cho Sanghoon Jheon Jae Yong Park

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

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

Authors:
Mi Jeong Hong Shin Yup Lee Jin Eun Choi Hyo-Gyoung Kang Sook Kyung Do Jang Hyuck Lee Seung Soo Yoo Eung Bae Lee Yangki Seok Sukki Cho Sanghoon Jheon Jaehee Lee Seung Ick Cha Chang Ho Kim Jae Yong Park

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.

Authors:
Kyung Min Shin Mi Jeong Hong Shin Yup Lee Cheng Cheng Jin Sun Ah Baek Jang Hyuck Lee Jin Eun Choi Hyo-Gyoung Kang Won Kee Lee Yangki Seok Eung Bae Lee Ji Yun Jeong Seung Soo Yoo Jaehee Lee Seung Ick Cha Chang Ho Kim Young Chul Kim In Jae Oh Kook Joo Na Sukki Cho Sanghoon Jheon Jae Yong Park

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

Association between polymorphisms in microRNA target sites and survival in early-stage non-small cell lung cancer.

Authors:
Seung Soo Yoo Mi Jeong Hong Jang Hyuck Lee Jin Eun Choi Shin Yup Lee Jaehee Lee Seung Ick Cha Chang Ho Kim Yangki Seok Eungbae Lee Sukki Cho Sanghoon Jheon Jae Yong Park

Thorac Cancer 2017 11 18;8(6):682-686. Epub 2017 Sep 18.

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

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.
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http://dx.doi.org/10.1111/1759-7714.12478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5668488PMC
November 2017

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

Authors:
Soyeon Lee Hyo Gyoung Kang Jin Eun Choi Jang Hyuck Lee Hyo Jung Kang Sun Ah Baek Eungbae Lee Yangki Seok Won Kee Lee Shin Yup Lee Seung Soo Yoo Jaehee Lee Seung Ick Cha Chang Ho Kim Sukki Cho Jae Yong Park

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

Genetic Variants in the Wnt Signaling Pathway Are Not Associated with Survival Outcome of Non-Small Cell Lung Cancer in a Korean Population.

Authors:
Seung Soo Yoo Mi Jeong Hong Jin Eun Choi Jang Hyuck Lee Sun Ah Baek Won Kee Lee So Yeon Lee Shin Yup Lee Jaehee Lee Seung Ick Cha Chang Ho Kim Sukki Cho Jae Yong Park

J Korean Med Sci 2016 Mar 17;31(3):463-6. Epub 2016 Feb 17.

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

Recently, genetic variants in the WNT signaling pathway have been reported to affect the survival outcome of Caucasian patients with early stage non-small cell lung cancer (NSCLC). We therefore attempted to determine whether these same WNT signaling pathway gene variants had similar impacts on the survival outcome of NSCLC patients in a Korean population. A total of 761 patients with stages I-IIIA NSCLC were enrolled in this study. Eight variants of WNT pathway genes were genotyped and their association with overall survival and disease-free survival were analyzed. None of the eight variants were significantly associated with overall survival or disease-free survival. There were no differences in survival outcome after stratifying the subjects according to age, gender, smoking status, and histological type. These results suggest that genetic variants in the WNT signaling pathway may not affect the survival outcome of NSCLC in a Korean population.
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http://dx.doi.org/10.3346/jkms.2016.31.3.463DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4779874PMC
March 2016

Sudden hearing loss in chronic myelogenous leukaemia implicating the hyperviscosity syndrome.

Authors:
Sung Won Chae Jae Hoon Cho Jang Hyuck Lee Hee Joon Kang Soon Jae Hwang

J Laryngol Otol 2002 Apr;116(4):291-3

Department of Otolaryngology-Head and Neck Surgery, College of Medicine, Korea University, Seoul, Korea.

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.
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http://dx.doi.org/10.1258/0022215021910564DOI Listing
April 2002