• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.1053-1055
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• 2016

Background: Polycythemia rubra vera (PV), being a primary polycythemia, is caused by neoplastic proliferation of erythroid, megakaryocytic and granulocytic lineages which result in panmyelosis. PV patients have a somatic acquired mutation in the Janus kinase (JAK2) pathway, rendering cell proliferation independent of the normal regulatory mechanisms that regulate erythropoiesis. The rational of this study was to determine the prevalence of the JAK-2 V617F mutation in Pakistani patients with PV. Materials and Methods: In this cross sectional study, 26 patients with PV were enrolled from January 2010 to December 2014. Patients were diagnosed based on WHO criteria for PV. All were screened for G-T point mutation (V617F) in the JAK2 gene on chromosome 9 by an allele specific PCR. Results: The mean age was $53.4{\pm}9.31years$ (range 36-72) and the male to female ratio was 2:1. The frequency of JAK2 V617F positivity in our PV patients was found to be 92.3%. Overall 30.7% of patients were asymptomatic and remaining 69.3% presented with symptomatic disease. The mean hemoglobin was $18.1{\pm}1.9g/dl$ with the mean hematocrit of $55.6{\pm}8.3%$. The mean total leukocyte count was $12.8{\pm}7.1{\times}10^9/l$ and the platelet count was $511{\pm}341.9{\times}10^9/l$. A positive correlation of JAK2 V617F mutation was established with high TLC count (P=0.01). No correlation of JAK2 V617F could be established with age or gender (P>0.05). Conclusions: The JAK2 V617F mutation frequency in our PV patients was similar to those reported internationally. Screening for the mutation in all suspected PV cases could be beneficial in differentiating patients with reactive and clonal erythrocytosis.

• BMB Reports
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• v.56 no.5
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• pp.265-274
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• 2023

Defects in DNA double-strand break (DSB) repair signaling permit cancer cells to accumulate genomic alterations that confer their aggressive phenotype. Nevertheless, tumors depend on residual DNA repair abilities to survive the DNA damage induced by genotoxic stress. This is why only isolated DNA repair signaling is inactivated in cancer cells. DNA DSB repair signaling contributes to general mechanism for various types of lesions in diverse cell cycle phases. DNA DSB repair genes are frequently mutated and amplified in cancer; however, limited data exist regarding the overall genomic prospect and functional result of these modifications. We list the DNA repair genes and related E3 ligases. Mutation and expression frequencies of these genes were analyzed in COSMIC and TCGA. The 11 genes with a high frequency of mutation differed between cancers, and mutations in many DNA DSB repair E3 ligase genes were related to a higher total mutation burden. DNA DSB repair E3 ligase genes are involved in tumor suppressive or oncogenic functions, such as RNF168 and FBXW7, by assisting the functionality of these genomic alterations. DNA damage response-related E3 ligases, such as RNF168, FBXW7, and HERC2, were generated with more than 10% mutation in several cancer cells. This study provides a broad list of candidate genes as potential biomarkers for genomic instability and novel therapeutic targets in cancer. As a DSB related proteins considerably appear the possibilities for targeting DNA repair defective tumors or hyperactive DNA repair tumors. Based on recent research, we describe the relationship between unstable DSB repairs and DSB-related E3 ligases.

• BMB Reports
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• v.51 no.9
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• pp.437-443
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• 2018

Non-homologous end joining (NHEJ), and to a lesser extent, the error-free pathway known as homology-directed repair (HDR) are cellular mechanisms for recovery from double-strand DNA breaks (DSB) induced by RNA-guided programmable nuclease CRISPR/Cas. Since NHEJ is equivalent to using a duck tape to stick two pieces of metals together, the outcome of this repair mechanism is prone to error. Any out-of-frame mutations or premature stop codons resulting from NHEJ repair mechanism are extremely handy for loss-of-function studies. Substitution of a mutation on the genome with the correct exogenous repair DNA requires coordination via an error-free HDR, for targeted transgenesis. However, several practical limitations exist in harnessing the potential of HDR to replace a faulty mutation for therapeutic purposes in all cell types and more so in somatic cells. In germ cells after the DSB, copying occurs from the homologous chromosome, which increases the chances of incorporation of exogenous DNA with some degree of homology into the genome compared with somatic cells where copying from the identical sister chromatid is always preferred. This review summarizes several strategies that have been implemented to increase the frequency of HDR with a focus on somatic cells. It also highlights the limitations of this technology in gene therapy and suggests specific solutions to circumvent those barriers.

• Genomics & Informatics
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• v.20 no.1
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• pp.10.1-10.15
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• 2022

Human exposure to pollutants has been on the rise. Thus, researchers have been focused on understanding the effect of these compounds on human health, especially on the genetic information by using various tests, among them the somatic mutation and recombination tests (SMARTs). It is a sensitive and accurate method applicable to genotoxicity analysis. Here, a comprehensive bibliometric analysis of SMART assays in genotoxicity studies was performed to assess publication trends of this field. Data were extracted from the Web of Science database and analyzed by the bibliometric tools HistCite, Biblioshiny (RStudio), VOSViewer, and CiteSpace. Results have shown an increase in the last 10 years in terms of publication. A total of 392 records were published in 96 sources mainly from Brazil, Spain, and Turkey. Research collaboration networks between countries and authors were performed. Based on document co-citation, five large research clusters were identified and analyzed. The youngest research frontier emphasized on nanoparticles. With this study, how research trends evolve over years was demonstrated. Thus, international collaboration could be enhanced, and a promising field could be developed.

• Clinical and Experimental Pediatrics
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• v.59 no.1
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• pp.40-42
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• 2016

Lynch syndrome is the most common inherited colon cancer syndrome. Patients with Lynch syndrome develop a range of cancers including colorectal cancer (CRC) and carry a mutation on one of the mismatched repair (MMR) genes. Although CRC usually occurs after the fourth decade in patients with Lynch syndrome harboring a heterozygous MMR gene mutation, it can occur in children with Lynch syndrome who have a compound heterozygous or homozygous MMR gene mutation. We report a case of CRC in a 13-year-old patient with Lynch syndrome and congenital heart disease. This patient had a heterozygous mutation in MLH1 (an MMR gene), but no compound MMR gene defects, and a K-RAS somatic mutation in the cancer cells.

• Proceedings of the Korean Nuclear Society Conference
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• 1999.05a
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• pp.387-387
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• 1999

• Genomics & Informatics
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• v.11 no.4
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• pp.239-244
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• 2013

Somatic mutation is a major cause of cancer progression and varied responses of tumors against anticancer agents. Thus, we must obtain and characterize genome-wide mutational profiles in individual cancer subtypes. The Cancer Genome Atlas database includes large amounts of sequencing and omics data generated from diverse human cancer tissues. In the present study, we integrated and analyzed the exome sequencing data from ~3,000 tissue samples and summarized the major mutant genes in each of the diverse cancer subtypes and stages. Mutations were observed in most human genes (~23,000 genes) with low frequency from an analysis of 11 major cancer subtypes. The majority of tissue samples harbored 20-80 different mutant genes, on average. Lung cancer samples showed a greater number of mutations in diverse genes than other cancer subtypes. Only a few genes were mutated with over 5% frequency in tissue samples. Interestingly, mutation frequency was generally similar between non-metastatic and metastastic samples in most cancer subtypes. Among the 12 major mutations, the TP53, USH2A, TTN, and MUC16 genes were found to be frequent in most cancer types, while BRAF, FRG1B, PBRM1, and VHL showed lineage-specific mutation patterns. The present study provides a useful resource to understand the broad spectrum of mutation frequencies in various cancer types.

• BMB Reports
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• v.49 no.2
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• pp.71-72
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• 2016

Focal cortical dysplasia type II (FCDII) is a focal malformation of the developing cerebral cortex and the major cause of intractable epilepsy. However, since the molecular genetic etiology of FCD has remained enigmatic, the effective therapeutic target for this condition has remained poorly understood. Our recent study on FCD utilizing various deep sequencing platforms identified somatic mutations in MTOR (existing as low as 1% allelic frequency) only in the affected brain tissues. We observed that these mutations induced hyperactivation of the mTOR kinase. In addition, focal cortical expression of mutant MTOR using in utero electroporation in mice, recapitulated the neuropathological features of FCDII, such as migration defect, cytomegalic neuron and spontaneous seizures. Furthermore, seizures and dysmorphic neurons were rescued by the administration of mTOR inhibitor, rapamycin. This study provides the first evidence that brain somatic activating mutations in MTOR cause FCD, and suggests the potential drug target for intractable epilepsy in FCD patients.

• Journal of Gastric Cancer
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• v.3 no.2
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• pp.84-87
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• 2003

Purpose: Evidence exists that dysregulation of Bcl-2 family members is involved in the pathogenesis of cancer development. The aim of this study was to explore whether the somatic mutation of proapoptotic Bcl-2 member genes, one of the mechanisms that prolong the survival of cancer cells, is involved in gastric carcinogenesis. Materials and Methods: In the current study, to detect somatic mutations of the DNA sequences encoding the Bcl-2 homology 3 (BH3) domain of the human BAD, BIM, BIK, and Bcl-G genes in 60 advanced gastric adenocarcinomas, we used the polymerase chain reaction (PCR), single strand conformation polymorphism (SSCP), and DNA sequencing. Results: The SSCP analysis revealed no mutations in the coding regions of the BH3 domain in the cancers. Conclusion: The data presented here indicate that proapoptotic Bcl-2 member genes, BAD, BIM, BIK, and Bcl-G, may not be mutated in human gastric carcinomas and suggest that these genes might be altered by mechanisms other mechanisms somatic mutation.

• Genomics & Informatics
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• v.19 no.4
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• pp.40.1-40.11
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• 2021

Mutation signatures represent unique sequence footprints of somatic mutations resulting from specific DNA mutagenic and repair processes. However, their causal associations and the potential utility for genome research remain largely unknown. In this study, we performed PanCancer-scale correlative analyses to identify the genomic features associated with tumor mutation burdens (TMB) and individual mutation signatures. We observed that TMB was correlated with tumor purity, ploidy, and the level of aneuploidy, as well as with the expression of cell proliferation-related genes representing genomic covariates in evaluating TMB. Correlative analyses of mutation signature levels with genes belonging to specific DNA damage-repair processes revealed that deficiencies of NHEJ1 and ALKBH3 may contribute to mutations in the settings of APOBEC cytidine deaminase activation and DNA mismatch repair deficiency, respectively. We further employed a strategy to identify feature-driven, de novo mutation signatures and demonstrated that mutation signatures can be reconstructed using known causal features. Using the strategy, we further identified tumor hypoxia-related mutation signatures similar to the APOBEC-related mutation signatures, suggesting that APOBEC activity mediates hypoxia-related mutational consequences in cancer genomes. Our study advances the mechanistic insights into the TMB and signature-based DNA mutagenic and repair processes in cancer genomes. We also propose that feature-driven mutation signature analysis can further extend the categories of cancer-relevant mutation signatures and their causal relationships.