TGFBI Promoter Methylation is Associated with Poor Prognosis in Lung Adenocarcinoma Patients

Seok, Yangki,Lee, Won Kee,Park, Jae Yong,Kim, Dong Sun Korean Society for Molecular and Cellular Biology 2019 Molecules and cells Vol.42 No.2

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide and has high rates of metastasis. Transforming growth factor beta-inducible protein (TGFBI) is an extracellular matrix component involved in tumour growth and metastasis. However, the exact role of TGFBI in NSCLC remains controversial. Gene silencing via DNA methylation of the promoter region is common in lung tumorigenesis and could thus be used for the development of molecular biomarkers. We analysed the methylation status of the TGFBI promoter in 138 NSCLC specimens via methylation-specific PCR and evaluated the correlation between TGFBI methylation and patient survival. TGFBI promoter methylation was detected in 25 (18.1%) of the tumours and was demonstrated to be associated with gene silencing. We observed no statistical correlation between TGFBI methylation and clinicopathological characteristics. Univariate and multivariate analyses showed that TGFBI methylation is significantly associated with poor survival outcomes in adenocarcinoma cases (adjusted hazard ratio = 2.88, 95% confidence interval = 1.19-6.99, P = 0.019), but not in squamous cell cases. Our findings suggest that methylation in the TGFBI promoter may be associated with pathogenesis of NSCLC and can be used as a predictive marker for lung adenocarcinoma prognosis. Further large-scale studies are needed to confirm these findings.

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

Lee, Won Kee,Lee, Shin Yup,Choi, Jin Eun,Seok, Yangki,Lee, Eung Bae,Lee, Hyun Cheol,Kang, Hyo‐,Gyoung,Yoo, Seung Soo,Lee, Myung Hoon,Cho, Sukki,Jheon, Sanghoon,Kim, Young Chul,Oh, In Jae,Na, Koo John WileySons Australia, Ltd 2017 Thoracic cancer Vol.8 No.3

<P><B>Background</B></P><P>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.</P><P><B>Methods</B></P><P>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.</P><P><B>Results</B></P><P>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.</P><P><B>Conclusions</B></P><P>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.</P>

Pri-let-7a-2 rs1143770C>T Associated with Prognosis of Surgically Resected Non-Small Cell Lung Cancer

( Yong Dae Lee ),( Kyung Min Shin ),( Deuk Kju Jung ),( Won Kee Lee ),( Hyewon Seo ),( So Yeon Lee ),( Seung Soo Yoo ),( Shin Yup Lee ),( Seung Ick Cha ),( Jaehee Lee ),( Chang Ho Kim ),( Yangki Seok 대한결핵 및 호흡기학회 2015 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.120 No.0

Background: Evidence indicates that the let-7 microRNA (miRNA) may be a prognostic factor in lung cancer. Genetic variation in miRNA precursors could influence the processing and expression of miRNAs, which could affect the prognosis of lung cancer. We aimed to investigate the impact of single nucleotide polymorphisms (SNPs) of pri-let-7 on the prognosis of non-small cell lung cancer (NSCLC). Methods: Seven hundred sixty-one patients with surgically resected NSCLC were included. The four SNPs (pri-let-7a-2 rs1143770 and rs629367, pri-let-7a-1 rs10739971, and pri-let-7f-2 rs17276588) were genotyped using a polymerase chain reaction-restriction fragment length polymorphism assay. The genotype associations with overall survival (OS) and disease-free survival (DFS) were evaluated. Results: Of the four SNPs analyzed, the rs1143770C>T was identified to be significantly associated with OS and DFS. The rs1143770 CT or TT genotype exhibited a significantly better OS and DFS compared with the rs1143770 CC genotype (adjusted hazard ratio for OS = 0.67, 95% confidence interval = 0.49―0.91, P = 0.01 and adjusted hazard ratio for DFS = 0.74, 95% confidence interval = 0.58―0.95, P = 0.02). Conclusions: This observation indicates that the pri-let-7a-2 rs1143770C>T may have a prognostic impact on surgically resected NSCLC.

Association between polymorphisms in micro RNA target sites and survival in early‐stage non‐small cell lung cancer

Yoo, Seung Soo,Hong, Mi Jeong,Lee, Jang Hyuck,Choi, Jin Eun,Lee, Shin Yup,Lee, Jaehee,Cha, Seung Ick,Kim, Chang Ho,Seok, Yangki,Lee, Eungbae,Cho, Sukki,Jheon, Sanghoon,Park, Jae Yong Wiley-Blackwells 2017 Thoracic Cancer Vol.8 No.6

<P>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.</P>

LKB1 pathway variant and the prognosis of non-small cell lung cancer after surgical resection

이용훈,( Sook Kyung Do ),( Shin Yup Lee ),( Hyo-gyoung Kang ),( Jin Eun Choi ),( Mi Jeong Hong ),( Jang Hyuck Lee ),( Eung Bae Lee ),( Yangki Seok ),( Ji Yun Jeong ),( Kyung Min Shin ),( Won Kee Lee ),( 대한결핵 및 호흡기학회 2018 대한결핵 및 호흡기학회 추계학술대회 초록집 Vol.126 No.-

This study was conducted to investigate the associations between polymorphisms of genes involved in LKB1 pathway and the prognosis of patients with non-small cell lung cancer (NSCLC) after surgical resection. Twenty-three single nucleotide polymorphisms (SNPs) in LKB1 pathway 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) were analyzed. Among the 23 SNPs investigated, TSC2 rs30259G>A was significantly associated with survival outcomes in multivariate analyses. The TSC2 rs30259G>A was associated with significantly worse OS and DFS (adjusted hazard ratio [aHR] for OS=1.88, 95% confidence interval [CI]=1.21-2.91, P=0.005; aHR for DFS=1.65, 95% CI=1.15-2.38, P=0.01, under codominant model, respectively). When stratified by tumor histology, the SNP was significantly associated with survival outcomes only in squamous cell carcinoma, but not in adenocarcinoma. This study suggests that TSC2 rs30259G>A may be useful for the prediction of prognosis in patients with early stage NSCLC after curative surgery.

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

Hong, Mi Jeong,Lee, Shin Yup,Choi, Jin Eun,Kang, Hyo‐,Gyoung,Do, Sook Kyung,Lee, Jang Hyuck,Yoo, Seung Soo,Lee, Eung Bae,Seok, Yangki,Cho, Sukki,Jheon, Sanghoon,Lee, Jaehee,Cha, Seung Ick,Kim, C Wiley-Blackwells 2018 Thoracic cancer Vol.9 No.8

<P><B>Background</B></P><P>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 <I>EGFR</I> gene region using RegulomeDB and their associations with prognosis after surgery in non‐small cell lung cancer (NSCLC) patients.</P><P><B>Methods</B></P><P>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.</P><P><B>Results</B></P><P>Among the seven SNPs evaluated, rs9642391 (<I>EGFR</I> 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, <I>P</I> = 0.001; adjusted HR for disease‐free survival = 0.82, 95% CI 0.70–0.97, <I>P</I> = 0.02; under a codominant model). According to RegulomeDB, rs9642391C>G, which is located in intron 19 of <I>EGFR</I>, was predicted to influence the expression of <I>GBAS</I> but not <I>EGFR</I>. As predicted, rs9642391C>G was associated with <I>GBAS</I> (<I>P</I> = 0.024) but not <I>EGFR</I> messenger RNA expression in tumor tissues.</P><P><B>Conclusion</B></P><P>In conclusion, our study provides evidence that rs9642391C>G in the intron of <I>EGFR</I> is associated with <I>GBAS</I> expression and survival outcomes of patients with surgically resected early‐stage NSCLC.</P>

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

Shin, Kyung Min,Hong, Mi Jeong,Lee, Shin Yup,Jin, Cheng Cheng,Baek, Sun Ah,Lee, Jang Hyuck,Choi, Jin Eun,Kang, Hyo-Gyoung,Lee, Won Kee,Seok, Yangki,Lee, Eung Bae,Jeong, Ji Yun,Yoo, Seung Soo,Lee, Jaeh Elsevier BV 2018 Gene Vol.646 No.-

<P><B>Abstract</B></P> <P><B>Background</B></P> <P>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.</P> <P><B>Method</B></P> <P>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.</P> <P><B>Results</B></P> <P>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 (<I>ERCC1</I> rs2298881C>A, <I>BRCA2</I> rs3092989G>A, <I>NELFE</I> rs440454C>T, <I>PPP2R4</I> rs2541164G>A, and <I>LTBP4</I> rs3786527G>A) in the validation set. In combined analysis, <I>ERCC1</I> rs2298881C>A, <I>BRCA2</I> rs3092989, <I>NELFE</I> rs440454C>T, and <I>PPP2R4</I> rs2541164G>A were significantly associated with OS and DFS (adjusted HR ·aHR· for OS=1.46, 0.62, 078, and 0.76, respectively; <I>P</I> =0.003, 0.002, 0.007, and 0.003 respectively; and aHR for DFS=1.27, 0.69, 0.86, and 0.82, respectively; <I>P</I> =0.02, 0.002, 0.03, and 0.008, respectively). The <I>LTBP4</I> rs3786527G>A was significantly associated with better OS (aHR=0.75; <I>P</I> =0.003).</P> <P><B>Conclusion</B></P> <P>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.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Five among 509 SNPs from RegulomeDB were validated in two independent cohorts. </LI> <LI> Five SNPs in the cancer-related pathway genes were independent prognostic factors. </LI> <LI> RegulomeDB is a practical tool for selecting functional SNPs in regulatory regions. </LI> </UL> </P>

Polymorphisms in cancer-related pathway genes and lung cancer

Lee, Shin Yup,Kang, Hyo-Gyoung,Choi, Jin Eun,Jung, Deuk Kju,Lee, Won Kee,Lee, Hyun Chul,Lee, So Yeon,Yoo, Seung Soo,Lee, Jaehee,Seok, Yangki,Lee, Eung Bae,Cha, Seung Ick,Cho, Sukki,Kim, Chang Ho,Lee, European Respiratory Society 2016 The European respiratory journal Vol.48 No.4

<P>We evaluated the associations between potentially functional variants in a comprehensive list of cancer-related genes and lung cancer in a Korean population.</P><P>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.</P><P>Among the 68 SNPs, three SNPs (corepressor interacting with RBPJ 1 (<I>CIR1</I>) rs13009079T>C, ribonucleotide reductase M1 (<I>RRM1</I>) rs1465952T>C and solute carrier family 38, member 4 (<I>SLC38A4</I>) rs2429467C>T) consistantly showed significant associations with lung cancer in the replication study. In combined analysis, adjusted odds ratio for <I>CIR1</I> rs13009079T>C, <I>RRM1</I> rs1465952T>C and <I>SLC38A4</I> rs2429467C>T were 0.69, 0.71 and 0.73, respectively (p=4×10<SUP>−5</SUP>, 0.01 and 0.001, respectively) under the dominant model. The relative mRNA expression level of <I>CIR1</I> was significantly associated with rs13009079T>C genotypes in normal lung tissues (ptrend=0.03).</P><P>These results suggest that the three SNPs, particularly <I>CIR1</I> rs13009079T>C, may play a role in the pathogenesis of lung cancer.</P>

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

Lee, Yong Hoon,Do, Sook Kyung,Lee, Shin Yup,Kang, Hyo‐,Gyoung,Choi, Jin Eun,Hong, Mi Jeong,Lee, Jang Hyuck,Lee, Eung Bae,Jeong, Ji Yun,Shin, Kyung Min,Lee, Won Kee,Seok, Yangki,Cho, Sukki,Yoo, S Wiley-Blackwells 2019 Thoracic Cancer Vol.10 No.2

<P>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, <I>TSC2</I> rs30259G > A was associated with significantly worse OS and DFS (adjusted hazard ratio for OS 1.88, 95% confidence interval 1.21–2.91, <I>P</I> = 0.005; adjusted hazard ratio for DFS 1.65, 95% confidence interval 1.15–2.38, <I>P</I> = 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 <I>TSC2</I> rs30259G > A may be useful to predict prognosis in patients with NSCLC, especially squamous cell carcinoma, after curative surgery.</P>