No Association between Promoter Polymorphism of STK11 Gene and Lung Cancer Risk in the Korean Population

성재숙,박경화,최종권,서재홍,신상원,김준석,김열홍,황영미,류정선 대한암학회 2009 Cancer Research and Treatment Vol.41 No.4

Purpose Serine-threonine kinase11 (STK11) was originally identified in 1997 as the causative mutation that’s responsible for Peutz-Jeghers Syndrome (PJS). Several recent studies have reported that the STK11 gene is an important human tumor suppressor gene in lung cancer. We evaluated the associations between the polymorphisms of the STK11 promoter region and the risk of lung cancer in 901 Koreans. Materials and Methods By direct sequencing, we first discovered three novel polymorphisms (-1,795 T>C, -981 C>T and -160 G>T) and four known polymorphisms (-1,580 C>T, -1,494 A>C, -881 A>G and -458 G>C) of the STK11 promoter region in 24 blood samples of 24 Korean lung cancer patients. Further genotype analyses were then performed on 443 lung cancer patients and 458 controls. Results We discovered three novel polymorphisms and we identified four known polymorphisms of the STK11 promoter region in a Korean population. Statistical analyses revealed that the genotypes and haplotypes in the STK11 gene were not significantly associated with the risk of lung cancer in a Korean population. Conclusion This is the first study that’s focused on the association of STK11 promoter polymorphisms and the risk of lung cancer in a Korean population. To evaluate the role of the STK11 gene for the risk of lung cancer, the genotypes of the STK11 promoter region (-1,795 T>C, -1,494 A>C and -160 G>T) were determined in 901 Koreans, yet the result revealed no significant difference between the lung cancer patients and the controls. These results suggest that the three promoter polymorphisms we studied are not important risk factors for the susceptibility to lung cancer in Koreans.

Discovery and Evaluation of Polymorphisms in the AKT2 and AKT3 Promoter Regions for Risk of Korean Lung Cancer

성재숙,김열홍,박경화,김승태 한국유전체학회 2012 Genomics & informatics Vol.10 No.3

AKT is a signal transduction protein that plays a central role in the tumorigenesis. There are 3 mammalian isoforms of this serine/threonine protein kinase-AKT1, AKT2, and AKT3-showing a broad tissue distribution. We first discovered 2 novel polymorphisms (AKT2 -9826 C/G and AKT3 -811 A/G), and we confirmed 6 known polymorphisms (AKT2 -9473 C/T, AKT2 -9151 C/T,AKT2 -9025 C/T, AKT2 -8618G/A, AKT3 -675 A/-, and AKT3 -244 C/T) of the AKT2 and AKT3 promoter region in 24 blood samples of Korean lung cancer patients using direct sequencing. To evaluate the role of AKT2 and AKT3 polymorphisms in the risk of Korean lung cancer, genotypes of the AKT2 and AKT3 polymorphisms (AKT2 -9826 C/G, AKT2 -9473 C/T, AKT2 -9151 C/T, AKT2 -9025 C/T,AKT2 -8618G/A, and AKT3 -675 A/-) were determined in 360 lung cancer patients and 360 normal controls. Statistical analyses revealed that the genotypes and haplotypes in the AKT2 and AKT3 promoter regions were not significantly associated with the risk of lung cancer in the Korean population. These results suggest that polymorphisms of the AKT2 and AKT3 promoter regions do not contribute to the genetic susceptibility to lung cancer in the Korean population.

No Association between PIK3CA Polymorphism and Lung Cancer Risk in the Korean Population

성재숙,박경화,김승태,서재홍,신상원,김준석,김열홍 한국유전체학회 2010 Genomics & informatics Vol.8 No.4

The PIK3CA gene, oncogenic gene located on human chromosome 3q26.3, is an important regulator of cell proliferation, death, motility and invasion. To evaluate the role of PIK3CA gene in the risk of Korean lung cancer, genotypes of the PIK3CA polymorphisms (rs11709323, rs2699895, rs3729679, rs17849074 and rs1356413) were determined in 423 lung cancer patients and 443 normal controls. Statistical analyses revealed that the genotypes and haplotypes in the PIK3CA gene were not significantly associated with the risk of lung cancer in the Korean population, suggesting that these PIK3CA polymorphisms do not contribute to the genetic susceptibility to lung cancer in the Korean population.

Association of Single Nucleotide Polymorphisms in PIM-1 Gene with the Risk of Korean Lung Cancer

김대식,성재숙,신은순,유정선,최인근,박경화,박용,김의배,박세종,김열홍 대한암학회 2008 Cancer Research and Treatment Vol.40 No.4

Purpose: The expression of the PIM-1 gene, which is a proto-oncogene that encodes a serine/threonine kinase, is associated with multiple cellular functions such as proliferation, differentiation, apoptosis and tumorigenesis. In particular, several studies have reported that the PIM-1 gene is associated with the development of lymphoma, leukemia and prostate cancer. Therefore, this study was conducted to evaluate the association between the single nucleotide polymorphisms in the PIM-1 gene and the risk of lung cancer occurrence in the Korean population. Materials and Methods: To evaluate the role of the PIM-1 gene in the development of lung cancer, the genotypes of the PIM-1 gene were determined in 408 lung cancer patients and 410 normal subjects. Results: We found that the T-C-T-C haplotypes of the PIM-1 gene (−1196 T>C, IVS4 +55 T>C, IVS4 +1416 T>A and +3684 C>A) were associated with an increased risk of lung cancer [adjusted odds ratio (aOR): 3.98; 95% CI: 1.24∼12.75, p-value: 0.020]. In particular, these haplotypes showed an increased risk of lung cancer in males (aOR: 5.67; 95% CI: 1.32∼24.30, p-value: 0.019) and smokers (aOR: 7.82; 95% CI: 1.75∼34.98, p-value: 0.007). Conclusions: The present results suggest that the T-C-T-C haplotype of the PIM-1 gene could influence the risk of developing smoking-related lung cancer in the Korean population. Additional functional studies with an larger sample sized analysis are warranted to reconfirm our findings.

Clinical Application of Targeted Deep Sequencing in Metastatic Colorectal Cancer Patients: Actionable Genomic Alteration in K-MASTER project

이영우,이수현,성재숙,정희준,임아름,김주원,최윤지,박경화,김열홍 대한암학회 2021 Cancer Research and Treatment Vol.53 No.1

Purpose Next-generation sequencing (NGS) can facilitate precision medicine approaches in metastatic colorectal cancer (mCRC) patients. We investigated the molecular profiling of Korean mCRC patients under the K-MASTER project which was initiated in June 2017 as a nationwide precision medicine oncology clinical trial platform which used NGS assay to screen actionable mutations. Materials and Methods As of 22 January 2020, total of 994 mCRC patients were registered in K-MASTER project. Targeted sequencing was performed using three platforms which were composed of the K-MASTER cancer panel v1.1 and the SNUH FIRST Cancer Panel v3.01. If tumor tissue was not available, cell-free DNA was extracted and the targeted sequencing was performed by Axen Cancer Panel as a liquid biopsy. Results In 994 mCRC patients, we found 1,564 clinically meaningful pathogenic variants which mutated in 71 genes. Anti-EGFR therapy candidates were 467 patients (47.0%) and BRAF V600E mutation (n=47, 4.7%), deficient mismatch repair/microsatellite instability–high (n=15, 1.5%), HER2 amplifications (n=10, 1.0%) could be incorporated with recently approved drugs. The patients with high tumor mutation burden (n=101, 12.7%) and DNA damaging response and repair defect pathway alteration (n=42, 4.2%) could be enrolled clinical trials with immune checkpoint inhibitors. There were more colorectal cancer molecular alterations such as PIK3CA, KRAS G12C, atypical BRAF, and HER2 mutations and even rarer but actionable genes that approved or ongoing clinical trials in other solid tumors. Conclusion K-MASTER project provides an intriguing background to investigate new clinical trials with biomarkers and give therapeutic opportunity for mCRC patients.

Can Serum be Used for Analyzing the KRASMutation Status in Patients with Advanced Colorectal Cancer?

김승태,장원진,Lihua Jin,성재숙,최윤지,김열홍 대한암학회 2015 Cancer Research and Treatment Vol.47 No.4

Purpose KRASmutations have been used widely as prognostic or predictive marker in patients withadvanced colorectal cancer (CRC). However, it may be difficult to obtain a tumor tissue foranalyzing the status of KRAS mutation in large proportion of patients with advanceddisease. Materials and MethodsWe obtained pairs of tumor and serum samples from 65 patients with advanced CRC,between March 2008 and July 2011. KRAS mutation status from the tumor samples wasanalyzed by genomic polymerase chain reaction and direct sequence, and KRASmutationstatus from the serum samples was determined by a genomic polymerase chain reaction–restriction fragment length polymorphism assay. ResultsKRAS mutations were detected in the serum samples of 26 patients and in the tumorsamples of 31 patients. KRAS mutation status in the serum and tumor samples wasconsistent in 44 of the 65 pairs (67.7%). There was a significant correlation between themutations detected in the serum sample and the mutations detected in the matched tumorsample (correlation index, 0.35; p < 0.004). Twenty-two of the 57 patients (38.5%) receivedanti-epidermal growth factor receptor therapy as any line therapy. There was no significantdifference in the overall survival (OS) in accordance to the status of KRASmutations in boththe serum and tumor samples (p > 0.05). In a multivariate analysis, liver metastasis andno cytoreductive operation were independent prognostic factors for decreased OS. ConclusionThe serum sample might alternatively be used when it is difficult to obtain

Clinical Implication of Concordant or Discordant Genomic Profiling Between Primary and Matched Metastatic Tissues in Patients with Colorectal Cancer

최정윤,최선호,이민혁,박영수,성재숙,장원진,김주원,최윤지,김진,김동식,이성호,석준희,박경화,김선한,김열홍 대한암학회 2020 Cancer Research and Treatment Vol.52 No.3

Purpose The purpose of this study was to identify the concordant or discordant genomic profiling between primary and matched metastatic tumors in patients with colorectal cancer (CRC) and to explore the clinical implication. Materials and Methods Surgical samples of primary and matched metastatic tissues from 158 patients (335 samples) with CRC at Korea University Anam Hospital were evaluated using the Ion AmpliSeq Cancer Hotspot Panel. We compared genetic variants and classified them as concordant, primary-specific, and metastasis-specific variants. We used a combination of principal components analysis and clustering to find genomic groups. Kaplan-Meier curves were used to appraise survival between genomic groups. We used machine learning to confirm the correlation between genetic variants and metastatic sites. Results A total of 282 types of deleterious non-synonymous variants were selected for analysis. Of a total of 897 variants, an average of 40% was discordant. Three genomic groups were yielded based on the genomic discrepancy patterns. Overall survival differed significantly between the genomic groups. The poorest group had the highest proportion of concordant KRAS G12V and additional metastasis-specific SMAD4. Correlation analysis between genetic variants and metastatic sites suggested that concordant KRAS mutations would have more disseminated metastases. Conclusion Driver gene mutations were mostly concordant; however, discordant or metastasis-specific mutations were present. Clinically, the concordant driver genetic changes with additional metastasis-specific variants can predict poor prognosis for patients with CRC.

An Association Study of Polymorphisms in JAK3 Gene with Lung Cancer in the Korean Population

유원백,정해윤,임승준,성재숙,박경화,유정선,신상원,김준석,서재홍,김열홍 대한암학회 2011 Cancer Research and Treatment Vol.43 No.2

Purpose The genetic alteration of the janus kinases (JAKs), non-receptor tyrosine kinase, is related to the development of human cancers. However, little is known about how the sequence variation of JAK3 contributes to the development of lung cancer. This study investigated whether polymorphisms at the promoter region of the JAK3 gene are associated with the risk of lung cancer in the Korean population. Materials and Methods A total of 819 subjects, including 409 lung cancer patients and 410 healthy controls were recruited. The SNaPshot assay and polymerase chain reaction-restriction fragment length polymorphism analysis were used, and logistic regression analyses were performed to characterize the association between polymorphisms of JAK3 and lung cancer risk. Results Three polymorphisms (-672 G>A, +64 A>G and +227 G>A) of JAK3 were analyzed for large-scale genotyping (n=819). Statistical analyses revealed that polymorphisms and haplotypes in the JAK3 gene were not significantly associated with lung cancer. Conclusion JAK3 gene was not significantly associated with the risk of lung cancer in the Korean population.

Genome-Wide Association Study of Lung Cancer in Korean Non-Smoking Women

김진희,홍윤철,박경희,임선희,최진은,성재숙,박주연,최이영,전효성,박재용,윤형규,김열홍,유병수,김영태,허혜진,정연준,김호,성숙환 대한의학회 2013 Journal of Korean medical science Vol.28 No.6

Lung cancer in never-smokers ranks as the seventh most common cause of cancer death worldwide, and the incidence of lung cancer in non-smoking Korean women appears to be steadily increasing. To identify the effect of genetic polymorphisms on lung cancer risk in non-smoking Korean women, we conducted a genome-wide association study of Korean female non-smokers with lung cancer. We analyzed 440,794 genotype data of 285 cases and 1,455 controls, and nineteen SNPs were associated with lung cancer development (P < 0.001). For external validation, nineteen SNPs were replicated in another sample set composed of 293 cases and 495 controls, and only rs10187911 on 2p16.3 was significantly associated with lung cancer development (dominant model, OR of TG or GG, 1.58, P =0.025). We confirmed this SNP again in another replication set composed of 546 cases and 744 controls (recessive model, OR of GG, 1.32, P = 0.027). OR and P value in combined set were 1.37 and < 0.001 in additive model, 1.51 and < 0.001 in dominant model, and 1.54 and < 0.001 in recessive model. The effect of this SNP was found to be consistent only in adenocarcinoma patients (1.36 and < 0.001 in additive model, 1.49 and < 0.001in dominant model, and 1.54 and < 0.001 in recessive model). Furthermore, after imputation with HapMap data, we found regional significance near rs10187911, and five SNPs showed P value less than that of rs10187911 (rs12478012, rs4377361, rs13005521,rs12475464, and rs7564130). Therefore, we concluded that a region on chromosome 2 is significantly associated with lung cancer risk in Korean non-smoking women.

Comparison of the Data of a Next-Generation Sequencing Panel from K-MASTER Project with That of Orthogonal Methods for Detecting Targetable Genetic Alterations

최윤지,최정윤,김주원,임아름,이영우,장원진,이수현,성재숙,정희준,이종원,강은주,김정선,임태규,김혜숙,김유정,안미선,김영생,박지현,임승택,조성심,조장호,신상원,박경화,김열홍 대한암학회 2022 Cancer Research and Treatment Vol.54 No.1

Purpose K-MASTER project is a Korean national precision medicine platform that screened actionable mutations by analyzing next-generation sequencing (NGS) of solid tumor patients. We compared gene analyses between NGS panel from the K-MASTER project and orthogonal methods. Materials and Methods Colorectal, breast, non–small cell lung, and gastric cancer patients were included. We compared NGS results from K-MASTER projects with those of non-NGS orthogonal methods (KRAS, NRAS, and BRAF mutations in colorectal cancer [CRC]; epidermal growth factor receptor [EGFR], anaplastic lymphoma kinase [ALK] fusion, and reactive oxygen species 1 [ROS1] fusion in non–small cell lung cancer [NSCLC], and Erb-B2 receptor tyrosine kinase 2 (ERBB2) positivity in breast and gastric cancers). Results In the CRC cohort (n=225), the sensitivity and specificity of NGS were 87.4% and 79.3% (KRAS); 88.9% and 98.9% (NRAS); and 77.8% and 100.0% (BRAF), respectively. In the NSCLC cohort (n=109), the sensitivity and specificity of NGS for EGFR were 86.2% and 97.5%, respectively. The concordance rate for ALK fusion was 100%, but ROS1 fusion was positive in only one of three cases that were positive in orthogonal tests. In the breast cancer cohort (n=260), ERBB2 amplification was detected in 45 by NGS. Compared with orthogonal methods that integrated immunohistochemistry and in situ hybridization, sensitivity and specificity were 53.7% and 99.4%, respectively. In the gastric cancer cohort (n=64), ERBB2 amplification was detected in six by NGS. Compared with orthogonal methods, sensitivity and specificity were 62.5% and 98.2%, respectively. Conclusion The results of the K-MASTER NGS panel and orthogonal methods showed a different degree of agreement for each genetic alteration, but generally showed a high agreement rate.