• Genomics & Informatics
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• v.20 no.1
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• pp.4.1-4.8
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• 2022

Loss of heterozygosity (LOH) is a genomic aberration. In some cases, LOH can be generated without changing the copy number, which is called copy-neutral LOH (CN-LOH). CN-LOH frequently occurs in various human diseases, including cancer. However, the biological and clinical implications of CN-LOH for human diseases have not been well studied. In this study, we compared the performance of CN-LOH determination using three commonly used tools. For an objective comparison, we analyzed CN-LOH profiles from single-nucleotide polymorphism array data from 10 colon adenocarcinoma patients, which were used as the reference for comparison with the CN-LOHs obtained through whole-exome sequencing (WES) data of the same patients using three different analysis tools (FACETS, Nexus, and Sequenza). The majority of the CN-LOHs identified from the WES data were consistent with the reference data. However, some of the CN-LOHs identified from the WES data were not consistent between the three tools, and the consistency with the reference CN-LOH profile was also different. The Jaccard index of the CN-LOHs using FACETS (0.84 ± 0.29; mean value, 0.73) was significantly higher than that of Nexus (0.55 ± 0.29; mean value, 0.50; p = 0.02) or Sequenza (0 ± 0.41; mean value, 0.34; p = 0.04). FACETS showed the highest area under the curve value. Taken together, of the three CN-LOH analysis tools, FACETS showed the best performance in identifying CN-LOHs from The Cancer Genome Atlas colon adenocarcinoma WES data. Our results will be helpful in exploring the biological or clinical implications of CN-LOH for human diseases.

• Journal of Korean Neurosurgical Society
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• v.48 no.1
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• pp.14-19
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• 2010

Objective : Allelic losses or loss of heterozygosity (LOH) at many chromosomal loci have been found in the cells of meningiomas. The objective of this study was to evaluate LOH at several loci of different chromosomes (1p32, 17p13, 7q21, 7q31, and 22q13) in different grades of meningiomas. Methods : Forty surgical specimens were obtained and classified as benign, atypical, and anaplastic meningiomas. After DNA extraction, ten polymorphic microsatellite markers were used to detect LOH. Medical and surgical records, as well as pathologic findings, were reviewed retrospectively. Results : LOH at 1p32 was detected in 24%, 60%, and 60% in benign, atypical, and anaplastic meningiomas, respectively. Whereas LOH at 7q21 was found in only one atypical meningioma. LOH at 7q31 was found in one benign meningioma and one atypical meningioma. LOH at 17p13 was detected in 4%, 40%, and 80% in benign, atypical, and anaplastic meningiomas, respectively. LOH at 22q13 was seen in 48%, 60%, and 60% in benign, atypical, and anaplastic meningiomas, respectively. LOH results at 1p32 and 17p13 showed statistically significant differences between benign and non-benign meningiomas. Conclusion : LOH at 1p32 and 17p13 showed a strong correlation with tumor progression. On the other hand, LOH at 7q21 and 7q31 may not contribute to the development of the meningiomas.

• Korean Journal of Clinical Laboratory Science
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• v.40 no.1
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• pp.41-47
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• 2008

Colorectal carcinoma is occurred frequently to Korean and so ranked the fourth from various cancers. Due to western dietary life, this cancer has been increased continually. Therefore, the study will be needed to find a candidate gene involved in the development and progression of colorectal carcinoma and to diagnose and treatment helpfully. The striking feature from cancer suppressor genes is known for LOH (loss of heterozygosity), which is the method to find allele genetic loss or mutation of cancer cell. The purpose of this study was designed to find a carcinogenic gene from colon cancer using microsatellite marker on 17th and 18th chromosome from 30 subjects. The LOH was investigated in order of D18S59 57% (17/30), TP53CA 50% (15/30), D18S68 47% (14/30), D18S69 43% (13/30). The genetic mutation depends on loci of colorectal carcinoma was shown higher with 2.44 from colon cancer than with 1.25 from right colorectal carcinoma (p<0.032). The genetic mutation with lymph nodes was investigated higher with 2.69 at mutated group than with 1.14 at non-mutated group (p<0.003). At genetic mutated pattern depends on disease stage, there was higher significant difference at III-IV stage 2.50 than that of I-II stage 1.17, respectively (p=0.015). There was no difference at comparison between histological classification and serological CEA increase. The loss on 18q21 found in this study is highly recurrence loci and was observed 43% for Korean with high recurrence. Therefore, LOH is a very useful tool to detect 18q21 loci in clinical application, prior to the treatment of colorectal carcinoma. After the operation of colorectol carcinoma, the efficient application using LOH at operated part tissue which is designed to protect the recurrence as well as its cure will be needed.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.6
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• pp.2489-2493
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• 2015

Background: Loss of heterozygosity (LOH) on chromosomal regions is crucial in tumor progression and this study aimed to identify genome-wide LOH in pancreatic cancer. Materials and Methods: Single-nucleotide polymorphism (SNP) profiling data GSE32682 of human pancreatic samples snap-frozen during surgery were downloaded from Gene Expression Omnibus database. Genotype console software was used to perform data processing. Candidate genes with LOH were screened based on the genotype calls, SNP loci of LOH and dbSNP database. Gene annotation was performed to identify the functions of candidate genes using NCBI (the National Center for Biotechnology Information) database, followed by Gene Ontology, INTERPRO, PFAM and SMART annotation and UCSC Genome Browser track to the unannotated genes using DAVID (the Database for Annotation, Visualization and Integration Discovery). Results: The candidate genes with LOH identified in this study were MCU, MICU1 and OIT3 on chromosome 10. MCU was found to encode a calcium transporter and MICU1 could encode an essential regulator of mitochondrial $Ca^{2+}$ uptake. OIT3 possibly correlated with calcium binding revealed by the annotation analyses and was regulated by a large number of transcription factors including STAT, SOX9, CREB, NF-kB, PPARG and p53. Conclusions: Global genomic analysis of SNPs identified MICU1, MCU and OIT3 with LOH on chromosome 10, implying involvement of these genes in progression of pancreatic cancer.

• Journal of the Korean Association of Oral and Maxillofacial Surgeons
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• v.37 no.6
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• pp.550-555
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• 2011

Chromosomal loss of heterozygosity (LOH) is a common mechanism for the inactivation of tumor suppressor genes in human epithelial cancers. LOH patterns can be generated through allelotyping using polymorphic microsatellite markers; however, owing to the limited number of available microsatellite markers and the requirement for large amounts of DNA, only a modest number of microsatellite markers can be screened. Hybridization to single nucleotide polymorphism (SNP) arrays using Affymetarix GeneChip Mapping 10 K 2.0 Array is an efficient method to detect genome-wide cancer LOH. We determined the presence of LOH in oral SCCs using these arrays. DNA was extracted from tissue samples obtained from 10 patients with tongue SCCs who presented at the Hospital of Tokyo Dental College. We examined the presence of LOH in 3 of the 10 patients using these arrays. At the locus that had LOH, we examined the presence of LOH using microsatellite markers. LOH analysis using Affymetarix GeneChip Mapping 10K Array showed LOH in all patients at the 1q31.1. The LOH regions were detected and demarcated by the copy number 1 with the series of three SNP probes. LOH analysis of 1q31.1 using microsatellite markers (D1S1189, D1S2151, D1S2595) showed LOH in all 10 patients (100). Our data may suggest that a putative tumor suppressor gene is located at the 1q31.1 region. Inactivation of such a gene may play a role in tongue tumorigenesis.

• Genomics & Informatics
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• v.1 no.2
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• pp.101-107
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• 2003

Loss of heterozygosity (LOH) has been used to detect deleted regions of a specific chromosome in cancer cells. LOH on chromosome 16q has been reported to occur frequently in progressed hepatocellular carcinoma (HCC). Liver tissues from 37 Korean HCC patients were analyzed for LOH by using 25 polymorphic microsatellite markers distributed along 16q. Out of the 37 HCC patients studied, 21 patients (56.8%) showed LOH in various regions of 16q with at least one polymorphic marker. Puring the analysis of these 21 LOH cases, 6 patients showed interstitial LOHs in which the boundary of the LOH region was defined. With two rounds of LOH analysis, five commonly occurring interstitial LOH regions were identified; 16q21-22.1, 16q22.2 - 22.3, 16q22.3, 16q23.2 and 16q23.3 - 24.1. Among the five LOH regions the 16q23.3 - 24.1 region has been reported to be related with chromosome instability. A complete physical map, which covers the 3.2 Mb region of 16q23.3 - 24.1 (D16S402 and D16S486), was constructed to identify novel candidate tumor suppressor genes. We provide the minimally tiling path map consisting of 28 BAC clones. There was one gap between NT_10422.11 and NT_019609.9 of the human genome sequence contig (NCBI sequence build 33, April 29, 2003). This gap can be filled by sequencing the R-1425M20 clone which bridges these sequence contigs.

• Tuberculosis and Respiratory Diseases
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• v.50 no.6
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• pp.668-675
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• 2001

Background : Non-smalll lung cancer(NSCLC) develops as a result of the accumulation of multiple genetic abnormalities. Loss of heterozygosity(LOH) is one of the most frequent genetic alterations that is found in NSCLC, and the chromosomal regions that display a high rate of LOH are thought to harbor tumor suppressor genes(TSGs). This study was done to determine the frequency of LOH in 21q with the aim of identifying potential TSG loci. Method : Thirty-nine surgically resected NSCLCs were analysed. Patients peripheral lymphocytes were used as the source of the normal DNA. Five microsatellite Inarkers of 21q were used to study LOH : 21q21.1(D21S1432, and D21S1994); 21q21.2-21.3(D21S1442) ; 21q22.1(21S1445) ; and 21q22.2-22.3(D21S266). The fractional allelic loss(FAL) in a tumor was calculated as the ratio of the number of markers showing LOH to the number of informative markers. Result : LOH for at least one locus was detected in 21 of 39 tumors(53.8%). Among the 21 tumors with LOH, 5(21.8%) showed LOH at almost all informative loci. Although statistically not significant, LOH was found more frequently in squamous cell carcinomas(15 of 23, 65.2%) than in adenocarcinomas(6 of 16, 37.5%). In the squamous cell carcinomas the frequency of LOH was higher in stage II-III (80.0%) than in stage I (53.8%). The FAL value in squamous cell carcinomas($0.431{\pm}0.375$) was significantly higher than that found in adenocarcinomas($0.l92{\pm}0.276$). Conclusion : These results suggest that LOH on 21q may be involved in the development of NSCLC, and that TSG(s) that contribute to the pathogenesis of NSCLC may exist on 21q.

• Korean Journal of Medicinal Crop Science
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• v.14 no.2
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• pp.96-100
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• 2006

Regions of allelic loss on chromosomes in many tumors of human and some experimental animals are generally considered to harbor tumor-suppressor genes involved in tumorigenesis. Allelotype analyses have greatly improved our under-standing of the molecular mechanism of radiation lymphomagenesis. Previously, we and others found frequent loss of heterozygosity (LOH) on chromosomes 4, 11, 12, 16 and 19 in radiation-induced lymphomas from several $F_1$, hybrid mice. To examine possible contributions of individual tumor-suppressor genes to tumorigenesis in p53 heterozygous deficiency, we investigated the genome-wide distribution and status of LOH in radiation-induced lymphomas from $F_1$ mice with different p53 status. In this study, we found frequent LOH (more than 20%) on chromosomes 4 and 12 and on chromosomes 11, 12, 16 and 19 in radiation-induced lymphomas from $(STS/A{\times}MSM/Ms)F_1$ mice and $(STS/A{\times}MSM/Ms)F_1-p53^{KO/+}$ mice, respectively. Low incidences of LOH (10-20%) were also observed on chromosomes 11 in mice with wild-type p53, and chromosomes 1, 2, 9, 17 and X in p53 heterozygous-deficient mice. The frequency of LOH on chromosomes 9 and 11 increased in the $(STS/A{\times}MSM/Ms)F_1-p53^{KO/+}$ mice. Preferential losses of the STS-derived allele on chromosome 9 and wild-type p53 allele on chromosome 11 were also found in the p53 heterozygous-deficient mice. Thus, the putative tumor-suppressor gene regions responsible for lymphomagenesis might considerably differ due to the p53 status.

• Proceedings of the Korean Society of Toxicology Conference
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• 2006.11a
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• pp.19-24
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• 2006

Mothers against decapentaplegic homolog 4 (SMAD4) is a tumor suppressor gene associated with gastrointestinal carcinogenesis. The aim of the present study was to characterize more precisely its role in the development and progression of human gastric carcinoma. In this study, using tissue microarray analysis of 283 gastric cancers and related lesions, we found loss of SMAD4 protein expression in the cytoplasm (36/114, 32%) and in the nucleus (46/114, 40%) of gastric cancer cells. The loss of nuclear SMAD4 expression in primary tumors correlated significantly with poor survival, and was an independent prognostic marker in multivariate analysis. We also found a substantial decrease in SMAD4 expression at both the RNA and protein level in several human gastric carcinoma cell lines. To identify the genetic and/or epigenetic mechanisms of altered SMAD4 expression in gastric carcinoma, loss of heterozygosity (LOH), promoter hypermethylation, and exon mutations were examined. We found that LOH (20/70, 29%) and promoter hypermethylation (4/73, 5%) were associated with the loss of SMAD4 expression. SMAD4 protein levels wore also affected in certain gastric carcinoma cell lines following incubation with Mc132, a proteasome inhibitor. Taken together, our results indicate that the loss of SMAD4, especially loss of nuclear SMAD4 expression, is involved in gastric cancer progression. The loss of SMAD4 in gastric carcinomas is due to several mechanisms, including LOH, hypermethylation, and proteasome degradation.

• Korean Journal of Head & Neck Oncology
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• v.14 no.1
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• pp.20-26
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• 1998

Objectives: Deletion in the short arm of chromosome 3 is common in many human cancers, including sporadic and hereditary renal carcinomas, small cell lung carcinomas, non-small cell lung carcinomas, and carcinomas of the ovary, breast, and cervix. A high frequency of chromosomal aberrations in head and neck cancers involving chromosome 3p has also been reported. These findings suggest that multiple tumor suppressor genes may be present on the short arm of chromosome 3. Materials and Methods: To investigate the possibility of chromosome 3p deletions in the Korean head and neck cancer patients, we applied a polymerase chain reaction(PCR)-based Restriction Fragment Length Polymorphism analysis to the DNA samples of matched normal mucosa and head and neck squamous cell carcinomas from 19 patients. Results: In the 19 normal samples heterozygosity at the polymorphic loci varied: 6 at the D3F15S2 locus(on telomeric 3p21), 2 at the D3S32 locus(on centromeric 3p21), and 4 at the THRB locus(on centromeric 3p24). In 12 matched carcinoma specimens, LOH(loss of heterozygosity) was observed at D3F15S2 in 1 of 6(17%), D3S32 in 1 of 2(50%), and at THRB in 2 of 4 cases(50%). Conclusion: The frequency of chromosome 3p deletion in the Korean head and neck carcinomas appear as other country did.