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Ji-Hong Kim,
Seung-Huyn Jung,
Joon Seol Bae,
Hye-Soon Lee,
Seon-Hee Yim,
So-Yeon Park,
So-Young Bang,
Hae-Jin Hu,
Hyoung Doo Shin,
Sang-Cheol Bae, Yeun-Jun Chung
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ABSTRACT: OBJECTIVE: Several copy number variations (CNVs) have been identified to be associated with systemic lupus erythematosus (SLE) through the target gene approach. However, genome-wide feature of CNVs and their roles in the risk of SLE remain unknown. We aimed to discover SLE-associated CNVs in Korean women. METHODS: We performed genome-wide assessments of CNVs in 382 SLE cases and 191 controls using Illumina HumanHap610 Chip. SLE-associated CNV regions (CNVRs) identified by a genome-wide association study (GWAS) were replicated by qPCR and deletion-typing PCR in an independent set comprising 564 SLEs and 511 controls. RESULTS: Out of 144 common CNVRs, three deletion-type CNVRs in 1q25.1, 8q23.3, and 10q21.3 were found to be significantly associated with SLE by GWAS analyses. In the independent replication, the CNVRs in 1q25.1 (RABGAP1L) and 10q21.3 were successfully replicated (OR=1.30, P=0.038 and OR=1.90, P=3.6x10(-5) , respectively) and the associations were confirmed again by deletion-typing PCR. The CNVR in C4 gene, which showed a potential association in the discovery stage, was included in the replication analysis and found to be significantly associated with the risk of SLE (OR=1.88, P=0.01). Through deletion-typing PCR, the exact sizes and breakpoint sequences of the deletions were defined. Individuals with the deletions in all three loci (RABGAP1L, 10q21.3 and C4) had a much higher risk than those without any deletions in all three loci (OR=5.52, P=3.9x10(-4) ). CONCLUSION: These CNVRs can be useful to identify the pathogenic mechanisms of SLE and to predict SLE risks more accurately by taking their synergistic effect into consideration.
Arthritis & Rheumatism 01/2013; · 7.87 Impact Factor
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ABSTRACT: Chromosomal alteration is one of the hallmarks of chronic myeloid leukemia (CML), and the Philadelphia chromosome is the most important and key example of the chromosomal changes in this disease. Indeed, the BCR-ABL1 fusion product is a target against which many tyrosine kinase inhibitors (TKIs) have been proven to be effective in the treatment of CML. However, the reality is that CML patients show resistance to TKIs both in an acquired and de novo manner, and the mechanism of TKI resistance is still largely unknown. This phenomenon suggests that in addition to the BCR-ABL mutation, further genetic alterations such as copy number aberration may be involved in unexplained TKI resistance. Although the recent array comparative genomic hybridization analyses (array-CGH) across the whole genome have detected multiple genetic aberrations in CML, the detailed feature of chromosomal alterations involved in different clinical phases of CML, such as chronic phase, accelerated phase, and blast crisis, remains unclear. Here we review the methodological aspects of array-CGH analysis for studying CML and its related data analysis.
Methods in molecular biology (Clifton, N.J.) 01/2013; 973:55-68.
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ABSTRACT: OBJECTIVES: A decrease in high-density lipoprotein (HDL) cholesterol during inflammation is common in many rheumatologic diseases, including rheumatoid arthritis (RA). Apolipoprotein M (apoM) is an apolipoprotein predominantly associated with HDL cholesterol. Recently, apoM polymorphisms have been related with RA susceptibility. We investigated the possible association between an APOM polymorphism and dyslipidaemia in Korean RA patients. METHODS: Two hundred and fifteen RA patients and 215 controls that provided complete genotyping were included. Genetic distribution, RA-associated phenotype, lipid profiles, and lipoproteins were evaluated. RESULTS: RA patients had increased frequencies of the APOM C-1065A A allele compared to the controls. RA patients with A/A genotypes had lower levels of HDL cholesterol than those with C/C genotypes. After adjustment for confounding factors, the A/A genotype was a risk factor for low HDL cholesterolaemia (OR=1.070, p=0.001). Subgroup analyses according to disease activity showed that the association between APOM genotype and HDL cholesterol levels was still significant in all subgroups, indicating that this APOM polymorphism may increase the dyslipidaemia risk, independently of RA disease activity. CONCLUSIONS: These data support that the APOM C-1065A polymorphism is associated with increased risk for developing RA and dyslipidaemia in RA patients. Reduced HDL cholesterol levels are independent of disease activity but are significantly influenced by APOM genotype. These findings suggest that a specific genetic factor for RA could be linked to dyslipidaemia and this could increase the risk of atherosclerosis in RA patients.
Clinical and experimental rheumatology 11/2012; · 2.15 Impact Factor
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ABSTRACT: In addition to single-nucleotide polymorphisms (SNP), copy number variation (CNV) is a major component of human genetic diversity. Among many whole-genome analysis platforms, SNP arrays have been commonly used for genomewide CNV discovery. Recently, a number of CNV defining algorithms from SNP genotyping data have been developed; however, due to the fundamental limitation of SNP genotyping data for the measurement of signal intensity, there are still concerns regarding the possibility of false discovery or low sensitivity for detecting CNVs. In this study, we aimed to verify the effect of combining multiple CNV calling algorithms and set up the most reliable pipeline for CNV calling with Affymetrix Genomewide SNP 5.0 data. For this purpose, we selected the 3 most commonly used algorithms for CNV segmentation from SNP genotyping data, PennCNV, QuantiSNP; and BirdSuite. After defining the CNV loci using the 3 different algorithms, we assessed how many of them overlapped with each other, and we also validated the CNVs by genomic quantitative PCR. Through this analysis, we proposed that for reliable CNV-based genomewide association study using SNP array data, CNV calls must be performed with at least 3 different algorithms and that the CNVs consistently called from more than 2 algorithms must be used for association analysis, because they are more reliable than the CNVs called from a single algorithm. Our result will be helpful to set up the CNV analysis protocols for Affymetrix Genomewide SNP 5.0 genotyping data.
Genomics & informatics. 09/2012; 10(3):194-9.
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ABSTRACT: BACKGROUND: The full extent of chromosomal alterations and their biological implications in early breast carcinogenesis has not been well examined. In this study, we aimed to identify chromosomal alterations associated with poor prognosis in early-stage breast cancers (EBC). METHODS: A total of 145 EBCs (stage I and II) were examined in this study. We analyzed copy number alterations in a discovery set of 48 EBCs using oligoarray-comparative genomic hybridization. In addition, the recurrently altered regions (RARs) associated with poor prognosis were validated using an independent set of 97 EBCs. RESULTS: A total of 23 RARs were defined in the discovery set. Six were commonly detected in both stage I and II groups (> 50%), suggesting their connection with early breast tumorigenesis. There were gains on 1q21.2-q21.3, 8q24.13, 8q24.13-21, 8q24.3, and 8q24.3 and a loss on 8p23.1-p22. Among the 23 RARs, copy number gains on 16p11.2 (NUPR1) and 17q12 (ERBB2) showed a significant association with poor survival (P = 0.0186 and P = 0.0186, respectively). The patients simultaneously positive for both gains had a significantly worse prognosis (P = 0.0001). In the independent replication, the patients who were double-positive for NUPR1-ERBB2 gains also had a significantly poorer prognosis on multivariate analysis (HR = 7.31, 95% CI 2.65-20.15, P = 0.0001). CONCLUSIONS: The simultaneous gain of NUPR1 and ERBB2 can be a significant predictor of poor prognosis in EBC. Our study will help to elucidate the molecular mechanisms underlying early-stage breast cancer tumorigenesis. This study also highlights the potential for using combinations of copy number alterations as prognosis predictors for EBC.
BMC Cancer 08/2012; 12(1):382. · 3.01 Impact Factor
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ABSTRACT: Developing diagnostic tools based on the application of known disease/phenotype-associated copy number variations (CNVs) requires the capacity to measure CNVs in a multiplex format with sufficient reliability and methodological simplicity. In this study, we developed a reliable and user-friendly multiplex CNV detection method, termed stuffer-free MLPA-CE-SSCP, that combines a variation of multiplex ligation-dependent probe amplification (MLPA) with CE-SSCP. In this variation, MLPA probes were designed without the conventionally required stuffer sequences. To separate the similar-sized stuffer-free MLPA products, we adopted CE-SSCP rather than length-dependent conventional CE analysis. An examination of the genomic DNA from five cell lines known to vary in X-chromosome copy number (1-5) revealed that copy number determinations using stuffer-free MLPA-CE-SSCP were more accurate than those of conventional MLPA, and the CV of the measured copy numbers was significantly lower. Applying our system to measure the CNVs on autosomes between two HapMap individuals, we found that all peaks for CNV targets showed the expected copy number changes. Taken together, our results indicate that this new strategy can overcome the limitations of conventional MLPA, which are mainly related to long probe length and difficulties of probe preparation.
Electrophoresis 07/2012; 33(19-20):3052-61. · 3.30 Impact Factor
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ABSTRACT: Large-scale copy number variants (CNVs) in the human provide the raw material for delineating population differences, as natural selection may have affected at least some of the CNVs thus far discovered. Although the examination of relatively large numbers of specific ethnic groups has recently started in regard to inter-ethnic group differences in CNVs, identifying and understanding particular instances of natural selection have not been performed. The traditional F(ST) measure, obtained from differences in allele frequencies between populations, has been used to identify CNVs loci subject to geographically varying selection. Here, we review advances and the application of multinomial-Dirichlet likelihood methods of inference for identifying genome regions that have been subject to natural selection with the F(ST) estimates. The contents of presentation are not new; however, this review clarifies how the application of the methods to CNV data, which remains largely unexplored, is possible. A hierarchical Bayesian method, which is implemented via Markov Chain Monte Carlo, estimates locus-specific F(ST) and can identify outlying CNVs loci with large values of F(ST). By applying this Bayesian method to the publicly available CNV data, we identified the CNV loci that show signals of natural selection, which may elucidate the genetic basis of human disease and diversity.
Genomics & informatics. 06/2012; 10(2):81-7.
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ABSTRACT: The method for genome-wide association study (GWAS) based on copy number variation (CNV) is not as well established as that for single nucleotide polymorphism (SNP)-GWAS. Although there are several tools for CNV association studies, most of them do not provide appropriate definitions of CNV regions (CNVRs), which are essential for CNV-association studies. Here we present a user-friendly program called CNVRuler for CNV-association studies. Outputs from the 10 most common CNV defining algorithms can be directly used as input files for determining the three different definitions of CNVRs. Once CNVRs are defined, CNVRuler supports four kinds of statistical association tests and options for population stratification. CNVRuler is based on the open-source programs R and Java from Sun Microsystems. AVAILABILITY: CNVRuler software is available with an online manual at the website, www.ircgp.com/CNVRuler/index.html.
Bioinformatics 04/2012; 28(13):1790-2. · 5.47 Impact Factor
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ABSTRACT: The presence of circulating tumor cells (CTCs) in patients with hepatocellular carcinoma (HCC) suggests metastasis to extra-hepatic
organs. Snail is a key regulator of epithelial mesenchymal transition, which is closely associated with tumor metastasis.
The aim of this study was to investigate the presence of CTCs and evaluate the significance of Snail mRNA levels in peripheral
blood of HCC patients with and without extra-hepatic metastasis. Sixty-six consecutive patients with HCC (30 without metastasis,
36 with metastasis) were prospectively enrolled, as were 30 with liver cirrhosis and 23 healthy subjects. CTCs were isolated
by FACS using Ber-EP4 and anti-CD45 antibodies, and CTC identity confirmed by immunofluorescent cytokeratin staining. Snail
mRNA levels were measured by quantitative real-time PCR of blood samples. CTCs, positive for pan-cytokeratin and Snail, were
isolated from five HCC patients with metastasis. The mean amount of Snail mRNA in HCC with metastasis was 18.8-fold, 26.6-fold
greater than HCC without metastasis, liver cirrhosis, respectively. When compared with healthy controls, the mean level of
Snail mRNA in HCC without metastasis was 10.1-fold greater (P<0.001). In six patients showing complete remission of HCC, Snail mRNA decreased to levels similar to those of healthy controls.
This study suggests the possibility that circulating Snail mRNA levels may have been associated with extra-hepatic metastasis
in HCC patients.
Clinical and Experimental Metastasis 04/2012; 26(7):759-767. · 3.52 Impact Factor
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Seon-Ah Ha,
Youn Soo Lee,
Seung Min Shin,
Hyun Kee Kim,
Sanghee Kim,
Hong Namkoong,
Hae Joo Kim,
Sang Min Jung,
Yu Sun Lee, Yeun Jun Chung,
Sang Seol Jung,
Jin Woo Kim
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ABSTRACT: BackgroundOncoprotein HCCR-1 functions as a negative regulator of the p53 and contributes breast tumorigenesis. The serum HCCR-1 assay
is useful in diagnosing breast cancer and mice transgenic for HCCR developed breast cancers. But it is unknown how HCCR-1 contributes to human breast tumorigenesis.
MethodsOncogene HCCR-1 expression levels were determined in normal breast tissues, breast cancer tissues and cancer cell lines. We
examined whether HCCR-1 protein expression in breast cancer is related to different biological characteristics, including
ER, PR, p53 genotype, and HER2 status in 104 primary breast cancer tissues using immunohistochemical analyses.
ResultsHCCR-1 was upregulated in breast cancer cells and tissues compared with normal breast tissues. In this study, overexpression
of HCCR-1 was well correlated with known breast cancer prognostic markers including the presence of steroid receptors (ER
and PR), p53 mutation and high HER2 overexpression. HCCR-1 was not detected in the ER-negative, PR-negative, p53 negative
and low HER2 breast cancer tissues. These data indicate that the level of HCCR-1 in breast cancer tissues is relatively well
correlated with known breast cancer factors, including the HER2 overexpression, p53 mutation, and ER/PR status.
ConclusionDetermination of HCCR-1 levels as options for HER2 testing is promising although it needs further evaluation.
BMC Cancer 04/2012; 9(1):1-6. · 3.01 Impact Factor
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ABSTRACT: We have discovered copy number variations (CNVs) in 3,578 Korean individuals with the Affymetrix Genome-Wide SNP array 5.0, and 4,003 copy number variation regions (CNVRs) were defined in a previous study. To explore the details of the variants easily in related studies, we built a database, cataloging the CNVs and related information. This system helps researchers browsing these variants with gene and structure variant annotations. Users can easily find specific regions with search options and verify them from system-integrated genome browsers with annotations.
Genomics & informatics. 03/2012; 10(1):65-7.
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ABSTRACT: The H1N1 influenza virus has spread worldwide to become pandemic. Here, we developed a new method to discriminate various types of influenza A, including H1N1, using stuffer-free multiplex ligation-dependent probe amplification based on a conformation-sensitive separation method, namely capillary electrophoresis-single-strand conformation polymorphism. Unlike conventional methods, our approach precisely detects five relevant gene markers permitting confirmation of infection.
Analytical Biochemistry 02/2012; 424(1):54-6. · 3.00 Impact Factor
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08/2011; , ISBN: 978-953-307-493-1
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ABSTRACT: Although the genetic component in the etiology of rheumatoid arthritis (RA) has been consistently suggested, many novel genetic loci remain to uncover. To identify RA risk loci, we performed a genome-wide association study (GWAS) with 100 RA cases and 600 controls using Affymetrix SNP array 5.0. The candidate risk locus (APOM gene) was re-sequenced to discover novel promoter and coding variants in a group of the subjects. Replication was performed with the independent case-control set comprising of 578 RAs and 711 controls. Through GWAS, we identified a novel SNP associated with RA at the APOM gene in the MHC class III region on 6p21.33 (rs805297, odds ratio (OR) = 2.28, P = 5.20 × 10-7). Three more polymorphisms were identified at the promoter region of the APOM by the re-sequencing. For the replication, we genotyped the four SNP loci in the independent case-control set. The association of rs805297 identified by GWAS was successfully replicated (OR = 1.40, P = 6.65 × 10-5). The association became more significant in the combined analysis of discovery and replication sets (OR = 1.56, P = 2.73 × 10-10). The individuals with the rs805297 risk allele (A) at the promoter region showed a significantly lower level of APOM expression compared with those with the protective allele (C) homozygote. In the logistic regressions by the phenotype status, the homozygote risk genotype (A/A) consistently showed higher ORs than the heterozygote one (A/C) for the phenotype-positive RAs. These results indicate that APOM promoter polymorphisms are significantly associated with the susceptibility to RA.
Experimental and Molecular Medicine 08/2011; 43(11):613-21. · 2.48 Impact Factor
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ABSTRACT: Structural variation of human genome such as duplications and deletions, collectively termed copy number variation (CNV), is one of the major genetic variations. Reliable and efficient measurement of CNV will be essential to develop diagnostic tools for CNV-related diseases. We established a strategy based on multiplex PCR and capillary electrophoresis (CE) for reliable CNV assay. Multiplex-PCR was performed using five primer sets for target loci and a diploid control (DC). We designed primers satisfying three conditions: different size of each PCR product for CE separation, unified annealing temperature for multiplex PCR, and suitability for quantitative PCR (qPCR). We defined the accurate PCR cycles for quantification of copy numbers at which the amplifications for all targets were supposed to be exponential, named maximum doubling cycle. CE was carried out with PCR product and the ratio of the peak areas (target/diploid control) was calculated. Our multiplex PCR-CE analysis reliably determined copy numbers of X chromosome with variable copies ranging from 1 to 5 and showed higher reliability than qPCR (correlation coefficient 0.996 versus 0.898). When measuring the six randomly selected autosomal CNV targets using our multiplex PCR-CE, the results agreed with those from qPCR. In addition, our strategy was validated for the broad application to commonly used CE devices. Taken together, this assay will be useful for accurate analysis of multiple disease-associated CNVs in a clinical setting.
Electrophoresis 06/2011; 32(14):1837-43. · 3.30 Impact Factor
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ABSTRACT: Comparative genomic hybridization (CGH) microarrays.
To identify genomic copy number variations (CNVs) in degenerative lumbar scoliosis (DLS) patients, and investigate the possibility of genetic predisposition in DLS.
Genome scanning technology enables search for presence of CNVs. CGH microarray is a useful procedure in a genome-wide study.
Among 45 consecutive patients who were diagnosed as DLS, 15 patients who manifested greatest Cobb's angle were selected for the array-CGH based CNV analysis. Control group was blood samples from 58 individuals without DLS. Oligonucleotide CGH microarray was utilized to analyze the CNV. Gene searches were performed for CNV DNA with significant gene-dosage difference. Validation qualitative PCR(qPCR) was performed at 3 genetic loci: at chromosome 2--TMEM163 gene, at chromosome 16--ANKRD 11 gene, and at chromosome 18--NFATC1 gene.
Genomic gains and losses were observed using the oligonucleotide CGH microarray. Identified CNVs were 446 ± 129 per individual. Gain- and loss-CNVs were identified as 196 ± 24 and 250 ± 110, respectively. The length of total CNV per individual was 30,946,730 ± 31,658,175 bp, and mean CNV-length was 61,017 ± 40,620 (median length 6411 ± 1994). Comparison with control group revealed 260 CNVs, which were significant (P < 10(-3)). Validation qPCR for gene-dosage comparison of DLS group DNA versus control group DNA in TMEM163 (P < 0.001); ANKRD 11 (P = 0.000); and NFATC1 (P = 0.000) gene showed significant difference.
Various whole-genome CNVs specific to DLS patients were observed. Validation qPCR confirmed significantly different gene-dosages for TMEM163, ANKRD 11, and NFATC1 genes. We consider that the expression of DLS is supported by various typical CNV-associated structural variants of the genome.
Spine 05/2011; 36(21):1782-93. · 2.08 Impact Factor
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ABSTRACT: Polo-like kinase 1 (Plk1), a serine-threonine kinase, plays a key role in the regulation of the cell cycle. Elevated Plk1 expression in various cancers is correlated with poor prognosis and poor patient survival rates. Several Plk1 inhibitors are currently being developed as potential treatments for cancer. In the present study, we investigated whether dendritic cells (DC) electroporated with mouse Plk1RNA (mPlk1RNA/DC) can induce Plk1-specific immune responses and exert antitumor effects in various murine tumor models. Overexpression of Plk1 protein was confirmed in several mouse and human tumor cell lines and various cancer tissues. Furthermore, Plk1-specific CD4(+) and CD8(+) T cells were induced by vaccination with mPlk1RNA/DC and the cytotoxic activity of the T cells was demonstrated against several Plk1-expressing tumor cell lines. Vaccination with mPlk1RNA/DC inhibited the growth of MC-38 and B16F10 tumors in C57BL/6 mice and the growth of CT26 tumors in BALB/c mice. Depletion of CD8(+) T cells reversed the inhibition of tumor growth by mPlk1RNA/DC vaccination. Homologous human Plk1RNA-electroporated DC also inhibited tumor growth in MC-38 tumor-bearing mice. In addition, Plk1-specific cytotoxic T lymphocytes from PBMC of healthy donors could be induced using autologous monocyte-derived DC electroporated with RNA encoding the whole gene of human Plk1. Taken together, the results of the present study suggest that Plk1 could be a universal tumor antigen recognized by cytotoxic T lymphocytes for cancer immunotherapy.
Cancer Science 05/2011; 102(8):1448-54. · 3.33 Impact Factor
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Joon Seol Bae,
Hyun Sub Cheong,
Ji-Hong Kim,
Byung Lae Park,
Jeong-Hyun Kim,
Tae Joon Park,
Jason Yongha Kim,
Charisse Flerida A Pasaje,
Jin Sol Lee,
Yun-Ju Park,
Miey Park,
Chan Park,
InSong Koh, Yeun-Jun Chung,
Jong-Young Lee,
Hyoung Doo Shin
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ABSTRACT: Unlike Caucasian populations, genetic factors contributing to the risk of type 2 diabetes mellitus (T2DM) are not well studied in Asian populations. In light of this, and the fact that copy number variation (CNV) is emerging as a new way to understand human genomic variation, the objective of this study was to identify type 2 diabetes-associated CNV in a Korean cohort.
Using the Illumina HumanHap300 BeadChip (317,503 markers), genome-wide genotyping was performed to obtain signal and allelic intensities from 275 patients with type 2 diabetes mellitus (T2DM) and 496 nondiabetic subjects (Total n = 771). To increase the sensitivity of CNV identification, we incorporated multiple factors using PennCNV, a program that is based on the hidden Markov model (HMM). To assess the genetic effect of CNV on T2DM, a multivariate logistic regression model controlling for age and gender was used. We identified a total of 7,478 CNVs (average of 9.7 CNVs per individual) and 2,554 CNV regions (CNVRs; 164 common CNVRs for frequency>1%) in this study. Although we failed to demonstrate robust associations between CNVs and the risk of T2DM, our results revealed a putative association between several CNVRs including chr15:45994758-45999227 (P = 8.6E-04, P(corr) = 0.01) and the risk of T2DM. The identified CNVs in this study were validated using overlapping analysis with the Database of Genomic Variants (DGV; 71.7% overlap), and quantitative PCR (qPCR). The identified variations, which encompassed functional genes, were significantly enriched in the cellular part, in the membrane-bound organelle, in the development process, in cell communication, in signal transduction, and in biological regulation.
We expect that the methods and findings in this study will contribute in particular to genome studies of Asian populations.
PLoS ONE 01/2011; 6(4):e19091. · 4.09 Impact Factor
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ABSTRACT: To explore the expression pattern of E2F5 in primary hepatocellular carcinomas (HCCs) and elucidate the roles of E2F5 in hepatocarcinogenesis.
E2F5 expression was analyzed in 120 primary HCCs and 29 normal liver tissues by immunohistochemistry analysis. E2F5-small interfering RNA was transfected into HepG2, an E2F5-overexpressed HCC cell line. After E2F5 knockdown, cell growth capacity and migrating potential were examined.
E2F5 was significantly overexpressed in primary HCCs compared with normal liver tissues (P = 0.008). The E2F5-silenced cells showed significantly reduced proliferation (P = 0.004). On the colony formation and soft agar assays, the number of colonies was significantly reduced in E2F5-silenced cells (P = 0.004 and P = 0.009, respectively). E2F5 knockdown resulted in the accumulation of G0/G1 phase cells and a reduction of S phase cells. The number of migrating/invading cells was also reduced after E2F5 knockdown (P = 0.021).
To our knowledge, this is the first evidence that E2F5 is commonly overexpressed in primary HCC and that E2F5 knockdown significantly repressed the growth of HCC cells.
World Journal of Gastroenterology 01/2011; 17(4):470-7. · 2.47 Impact Factor
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Youngil Koh,
Dae-Young Kim,
Sung-Hyo Park,
Seung-Hyun Jung,
Eunkyung Park,
Hyeoung-Joon Kim,
Sang Kyun Sohn,
Young Don Joo,
Seok Jin Kim,
Ho-Jin Shin,
Sung-Hyun Kim,
Hong Suk Song,
Jooseop Chung,
Inho Kim,
Sung-Soo Yoon,
Byoung Kook Kim,
Seung-Hun Shin, Yeun-Jun Chung,
Seonyang Park
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ABSTRACT: In a study population of 45 patients who were previously enrolled in an imatinib dose escalation trial, genome-wide screening for regions of genetic gains and losses was performed using array comparative genomic hybridization (aCGH). Early molecular response (EMR), defined as >50% reduction in the ratio of BCR-ABL1 to ABL1 within 6 months after dose escalation, was a major endpoint for analysis. After aCGH analysis, copy number change of four genes was investigated in 52 patients as a validation. Copy number gain in 16p11.2 was more frequently observed in patients with EMR than in patients who failed to achieve EMR (P = 0.034). A tendency for increased copy number in 22q11.23 in patients without EMR and for decreased copy number in 17q12 in patients with EMR was observed (P = 0.072 and P = 0.070, respectively). For GSTT1, in 22q11.23, copy number gain was observed in patients without EMR (P = 0.035). GSTT1 copy number gain was related to short time to treatment failure (TTFx) in patients without BCR-ABL1 mutations (P = 0.007). In multivariate analysis, GSTT1 copy number gain was an independent predictive factor for short TTFx (P = 0.020). We conclude that chromosome regions 16p11.2, 22q11.23, and 17q12 are potential locations related to response in imatinib dose escalation therapy for CML. GSTT1 copy number gain is a genetic change affecting outcome in this setting.
Cancer genetics and cytogenetics 12/2010; 203(2):215-21. · 1.54 Impact Factor
