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Kim H.,Hallym University | Cho D.-Y.,LabGenomics Clinical Research Institute | Choi D.H.,Sungkyunkwan University | Choi S.-Y.,LabGenomics Clinical Research Institute | And 10 more authors.
Breast Cancer Research and Treatment | Year: 2012

This investigation is aimed at evaluating the epidemiologic characteristics of BRCA1/2 germline mutations in Korean patients with breast and ovarian cancer (BOC). We analyzed the entire mutational data of BRCA1/2 genes in BOC patients who were tested in Korea since the first Korean report of BRCA1 mutation in 1995 with the exception of the data covered in the Korean Hereditary Breast Cancer (KOHBRA) study, the project launched in 2007 for establishing BRCA1/2 carrier cohorts in Korea. In total, BRCA1/2 gene mutations of 3,922 Korean BOC patients were evaluated, including the unpublished data of 2,139 breast cancer patients examined by four Korean institutions and the data of 1,783 BOC patients covered in ten previous reports. Overall, 420 (150 distinct) pathogenic mutations were identified, 211 (73 distinct) in BRCA1 and 209 (77 distinct) in BRCA2. The majority (134 of 150) of the distinct mutations resulted in premature termination codon of the BRCA1/2 translation. BRCA1 c.4186-1593-4676-1465del was the only large genomic rearrangements mutation. Out of 150 distinct BRCA1/2 mutations, 84 (56 %) mutations were considered specific to Korean BOC. Eighty-five BRCA1/2 mutations were detected in at least two unrelated patients. These recurrent mutations account for 84.5 % (355 of 420) of mutations detected in the Korean population. In the pooled mutational data of BRCA1/2 genes, this study discovered the prevalence of BRCA1/2 mutations in the Korean BOC patients is similar to those found in other ethnic groups. Large genomic rearrangements in BRCA1/2 genes were infrequently detected among the Korean patients with BOC. There were several BRCA1/2 mutation candidates for founder mutations. To further establish a Korean cohort for BRCA1/2 mutations, the nationwide KOHBRA study is in progress. © Springer Science+Business Media, LLC. 2012.


Cho S.-C.,Seoul National University | Kim J.-W.,Seoul National University | Kim H.-W.,University of Ulsan | Kim B.-N.,Seoul National University | And 5 more authors.
Psychiatric Genetics | Year: 2011

Complex phenotypes such as performance on the continuous performance test (CPT) are likely to exhibit epistasis. Genetic polymorphisms of noradrenergic system and brain-derived neurotrophic factor (BDNF), which participates in the differentiation and survival of noradrenergic neurons, have been reported to be associated with the performance on CPT. We evaluated the effect of the adrenergic α-2A receptor (ADRA2A) and BDNF gene-gene interaction on performance on the CPT in a Korean population with attention-deficit/ hyperactivity disorder. In all, 122 participants with attention-deficit/ hyperactivity disorder (8.6±2.3 years, 104 boys and 18 girls) completed the CPT. The DraI polymorphism of ADRA2A (rs583668) and rs11030101 polymorphism of BDNF were genotyped. Significant interaction effect was found of ADRA2A rs553668 and BDNF rs11030101 on response time variability (P=0.011) of the CPT. Our study provides preliminary evidence for the effect of the BDNF and ADRA2A gene-gene interaction on performance on the CPT in attention-deficit/ hyperactivity disorder. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Cho S.-C.,Seoul National University | Kim H.-W.,Seoul National University | Kim B.-N.,Seoul National University | Kim J.-W.,Seoul National University | And 8 more authors.
Progress in Neuro-Psychopharmacology and Biological Psychiatry | Year: 2010

Objective: Attention-deficit/hyperactivity disorder (ADHD) is a complex neurodevelopmental disorder with a strong genetic component. Neurotrophin-3 (NTF3), which participates in the differentiation and survival of dopaminergic and noradrenergic neurons, has been identified as a factor in the development of ADHD. We investigated the relationships between ADHD and NTF3 gene polymorphism. Methods: We conducted a case-control analysis of 202 ADHD subjects and 159 controls, performed a transmission disequilibrium test (TDT) on 151 trios, and compared the intelligence quotient (IQ) and a continuous performance test (CPT) according to the genotype of two single-nucleotide polymorphisms (SNPs) (rs6332 and rs6489630) in the NTF3 gene. Results: In the case-control and family-based analyses, NTF3 was not significantly associated with ADHD. However, in the ADHD probands, the subjects with AA genotype in the rs6332 SNP had significantly higher mean T-scores for commission errors on the CPT than did those with the AG genotypes (p= 0.045). The mean IQ of the ADHD probands who had the CC genotype of the rs6489630 SNP were higher compared with those who had the CT or TT genotype (p= 0.035). The mean T-score for response time on the CPT was higher in the subjects with TT genotype in the rs6489630 SNP compared to those with the CC or CT genotype, even after adjusting for the effect of IQ (p= 0.021). Conclusions: These results provide preliminary evidence of an association between NTF3 and the intelligence and selective attention deficit in the Korean population. © 2010 Elsevier Inc.


Noh J.M.,Sungkyunkwan University | Kim J.,LabGenomics Clinical Research Institute | Cho D.Y.,LabGenomics Clinical Research Institute | Choi D.H.,Sungkyunkwan University | And 2 more authors.
Radiation Oncology Journal | Year: 2015

Purpose: We performed exome sequencing in a breast cancer family without BRCA mutations. Materials and Methods: A family that three sisters have a history of breast cancer was selected for analysis. There were no family members with breast cancer in the previous generation. Genetic testing for BRCA mutation was negative, even by the multiplex ligation-dependent probe amplification method. Two sisters with breast cancer were selected as affected members, while the mother of the sisters was a non-affected member. Whole exome sequencing was performed on the HiSeq 2000 platform with paired-end reads of 101 bp in the three members. Results: We identified 19,436, 19,468, and 19,345 single-nucleotide polymorphisms (SNPs) in the coding regions. Among them, 8,759, 8,789, and 8,772 were non-synonymous SNPs, respectively. After filtering out 12,843 synonymous variations and 12,105 known variations with indels found in the dbSNP135 or 1000 Genomes Project database, we selected 73 variations in the samples from the affected sisters that did not occur in the sample from the unaffected mother. Using the Sorting Intolerant From Tolerant (SIFT), PolyPhen-2, and MutationTaster algorithms to predict amino acid substitutions, the XCR1, DLL1, TH, ACCS, SPPL3, CCNF, and SRL genes were risky among all three algorithms, while definite candidate genes could not be conclusively determined. Conclusion: Using exome sequencing, we found 7 variants for a breast cancer family without BRCA mutations. Genetic evidence of disease association should be confirmed by future studies. © 2015. The Korean Society for Radiation Oncology.


Kim J.H.,Korea Institute of Radiological and Medical Sciences | Choi D.H.,Sungkyunkwan University | Cho D.Y.,LabGenomics Clinical Research Institute | Ahn S.H.,University of Ulsan | And 2 more authors.
Breast Cancer Research and Treatment | Year: 2010

PALB2 is a recently discovered breast cancer susceptibility gene, and mutations in the gene have been demonstrated to confer about twofold higher risk of breast cancer. Truncating mutations in PALB2 gene have been identified in varied populations. However, PALB2's significance to breast cancer has not been investigated in the Korean population. In this study, we evaluated the frequency of PALB2 1592delT and 229delT mutations in 300 Korean breast cancer patients diagnosed with either familial or early-onset breast cancer. All patients were confirmed negative for BRCA1 and BRCA2 mutations. Neither 1592delT nor 229delT mutations was found in any of the study cohort. Our results imply that these mutations are absent or rare in Korean patients who are negative for BRCA1 and BRCA2 mutations. We found no evidence to recommend screening for these mutations in the Korean population. However, PALB2 mutations have been demonstrated infrequent and inhomogeneous across investigated populations. Thus, screening the whole PALB2 gene for novel mutations is required to elucidate its significance in predisposition to breast cancer in Korean women. © 2010 Springer Science+Business Media, LLC.


PubMed | LabGenomics Clinical Research Institute, Sungkyunkwan University and Hallym University
Type: | Journal: Breast cancer research and treatment | Year: 2016

This study was performed to evaluate the frequency of mutations in CHEK2, PALB2, MRE11, and RAD50 among Korean patients at high risk for hereditary breast cancer.A total of 235 Korean patients with hereditary breast cancer who tested negative for BRCA1/2 mutation were enrolled to this study. Entire coding regions of CHEK2, PALB2, MRE11, and RAD50 were analyzed using massively parallel sequencing (MPS). Sequence variants detected by MPS were confirmed by Sanger sequencing.Six patients (2.5%) were found to have pathogenic variants in CHEK2 (n=1), PALB2 (n=2), MRE11 (n=1), and RAD50 (n=2). Among the pathogenic variants, PALB2 c.2257C>T was previously reported in other studies, while CHEK2 c.1245dupC, PALB2 c.1048C>T, MRE11 c.1773_1774delAA, RAD50 c.1276C>T, and RAD50 c.3811_3813delGAA were newly identified in this study. A total of 15 missense variants were found in the four genes among 26 patients; 7 patients had a variant in CHEK2, 11 in PALB2, 2 in MRE11, and 6 in RAD50. When in silico analyses were performed to the 15 missense variants, six variants (CHEK2 c.686A>G, PALB2 c.1492G>T, PALB2 c.3054G>C, MRE11 c.140C>T, RAD50 c.1456C>T, and RAD50 c.3790C>T) were predicted to be deleterious.Pathogenic variants in CHEK2, PALB2, MRE11, and RAD50 were detected in a small proportion of Korean patients with features of hereditary breast cancer.


PubMed | LabGenomics Clinical Research Institute, Sungkyunkwan University and Hallym University
Type: Journal Article | Journal: Cancer research and treatment : official journal of Korean Cancer Association | Year: 2016

The aim of the current study is to assess the spectrum of genetic variation in the BRIP1 gene among Korean high-risk breast cancer patients who tested negative for the BRCA1/2 mutation.Overall, 235 Korean patientswith BRCA1/2 mutation-negative high-risk breast cancerwere screened for BRIP1 mutations. The entire BRIP1 gene was analyzed using fluorescent-conformation sensitive gel electrophoresis. In silico analysis of BRIP1 variants was performed using PolyPhen-2 and SIFT.A total of 20 sequence alterations including 12 exonic and eight intronic variantswere found. Among the 12 exonic variants, 10 were missense and two were silent mutations. No protein-truncating mutation was found among the tested patients. Among the 10 missense variants, four (p.L263F, p.L340F, p.L474P, and p.R848H) were predicted to be pathogenic by both PolyPhen-2 and SIFT, and these variants were found in five patients. Of the four missense variants, p.L263F, p.L474P, and p.R848H localize to regions between the helicase motifs, while p.L340F resides in an iron-sulfur domain of BRIP1.No protein-truncating mutation in BRIP1 was found among the tested patients. The contribution of BRIP1 variants is thought to be minor in Korean non-BRCA1/2 high-risk breast cancer.


Kim J.,Seoul National University | Kim J.,LabGenomics Clinical Research Institute | Kim K.,Seoul National University | Kim J.H.,Seoul National University
Computational and Mathematical Methods in Medicine | Year: 2016

Background. Interpretation of microarray data remains challenging because biological meaning should be extracted from enormous numeric matrices and be presented explicitly. Moreover, huge public repositories of microarray dataset are ready to be exploited for comparative analysis. This study aimed to provide a platform where essential implication of a microarray experiment could be visually expressed and various microarray datasets could be intuitively compared. Results. On the semantic space, gene sets from Molecular Signature Database (MSigDB) were plotted as landmarks and their relative distances were calculated by Lin's semantic similarity measure. By formal concept analysis, a microarray dataset was transformed into a concept lattice with gene clusters as objects and Gene Ontology terms as attributes. Concepts of a lattice were located on the semantic space reflecting semantic distance from landmarks and edges between concepts were drawn; consequently, a specific geographic pattern could be observed from a microarray dataset. We termed a distinctive geography shared by microarray datasets of the same category as "semantic signature." Conclusions. "Semantic space," a map of biological entities, could serve as a universal platform for comparative microarray analysis. When microarray data were displayed on the semantic space as concept lattices, "semantic signature," characteristic geography for a microarray experiment, could be discovered. © 2016 Jihun Kim et al.


PubMed | University of Ulsan and LabGenomics Clinical Research Institute
Type: Journal Article | Journal: Obstetrics & gynecology science | Year: 2015

To evaluate the performance of Momguard, non-invasive prenatal test (NIPT) for detecting trisomy (T) 21, T18, T13, and sex-chromosome abnormalities recently developed in Korea.This preliminary study formed part of a large prospective cohort study conducted at Asan Medical Center, Seoul, Korea. Only pregnant women who underwent both NIPT and confirmatory karyotyping were included in this study. NIPT results were compared with those of karyotype analyses.Among 93 eligible cases, NIPT results could not be obtained in one case due to a low fetal cell-free DNA fraction. Based on NIPT, eight cases of fetal aneuploidies, including T21 (n=5), T18 (n=2), and T13 (n=1), were identified. For T21 and T18, the sensitivity and specificity of NIPT were both 100%, with a false-positive and false-negative rate of 0% and a positive-predictive value of 100%. One patient classified as having intermediate risk for T13 by NIPT was confirmed to have T13 by karyotyping, and there were no false-negative cases. No cases of sex-chromosome anomalies were detected by NIPT or karyotyping during the study period.Momguard is a reliable screening tool for detecting T21 and T18. For T13 and sex-chromosome anomalies, further prospective studies are necessary to confirm its utility.


Kim E.J.,Chung Ang Medical Research Center | Jeong M.S.,Chung Ang Medical Research Center | Li K.,Chung - Ang University | Park M.K.,Chung - Ang University | And 4 more authors.
Annals of Dermatology | Year: 2011

Background: Filaggrin is a key protein that facilitates the formation of skin barrier by forming a stratum corneum. Mutations in the gene encoding filaggrin (FLG) have recently been reported in patients with ichthyosis vulgaris (IV). Interestingly, there are ethnic differences between FLG mutations identified in Asians and Europeans, and few FLG mutations are overlapping between Chinese and Japanese IV patients. Objective: The aim of this study was to investigative the genetic polymorphism of FLG in Korean IV patients. Methods: Genomic DNA was extracted from whole venous blood specimen of Korean patients with IV and a control group, and the full sequence of FLG was determined via overlapping long-range polymerase chain reaction method. Results: Analysis of base sequence previously unreported reveal new nonsense mutation p.Y1767X in a Korean IV patient, and additional new single nucleotide polymorphisms. Conclusion: On the basis of this study, it is anticipated that analysis of FLG gene sequence be extended to other dermatoses associated with FLG, such as atopic dermatitis.

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