• Molecular & Cellular Toxicology
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• 제3권4호
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• pp.262-266
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• 2007

ENPP2, a 125 kDa secreted lysophopholipase D which originally identified as a tumor-motogen, Autotaxin, enhances cellular locomotion, cell proliferation, angiogenesis and cell survival by generating the signal molecule lysophosphatic acid or sphingosine-1-phosphate. Previous studies have suggested that expression of Autotaxin is associated with invasive phenotype in advanced breast carcinomas. Thus, to determine whether genetic alterations of ENPP2 gene are involved in the development or progression of breast cancer, we analyzed its somatic mutation in 85 breast carcinomas by single-stranded conformational polymorphism and sequencing. Overall, six ENPP2 mutations were found (7.0%), comprising five missense and one nonsense mutation (s). To our knowledge, this is the first report on ENPP2 mutation in breast carcinoma, and the data indicate that ENPP2 is occasionally mutated in breast carcinomas, and suggest that ENPP2 mutation may contribute to the tumor development in some breast carcinomas.

• Journal of Gastric Cancer
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• 제3권2호
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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.

• Asian-Australasian Journal of Animal Sciences
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• 제27권3호
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• pp.324-329
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• 2014

To facilitate the construction of genetically-modified pigs, we produced cloned embryos derived from porcine fibroblasts transfected with a pair of engineered zinc finger nuclease (ZFN) plasmids to create targeted mutations and enriched using a reporter plasmid system. The reporter expresses RFP and eGFP simultaneously when ZFN-mediated site-specific mutations occur. Thus, double positive cells ($RFP^+/eGFP^+$) were selected and used for somatic cell nuclear transfer. Two types of reporter based enrichment systems were used in this study; the cloned embryos derived from cells enriched using a magnetic sorting-based system showed better developmental competence than did those derived from cells enriched by flow cytometry. Mutated sequences, such as insertions, deletions, or substitutions, together with the wild-type sequence, were found in the cloned porcine blastocysts. Therefore, genetic mutations can be achieved in cloned porcine embryos reconstructed with ZFN-treated cells that were enriched by a reporter-based system.

• Genomics & Informatics
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• 제11권4호
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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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• 제52권7호
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• pp.463-468
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• 2019

Autosomal dominant polycystic kidney disease (ADPKD), one of the most common human monogenic diseases (frequency of 1/1000-1/400), is characterized by numerous fluid-filled renal cysts (RCs). Inactivation of the PKD1 or PKD2 gene by germline and somatic mutations is necessary for cyst formation in ADPKD. To mechanistically understand cyst formation and growth, we isolated RCs from Korean patients with ADPKD and immortalized them with human telomerase reverse transcriptase (hTERT). Three hTERT-immortalized RC cell lines were characterized as proximal epithelial cells with germline and somatic PKD1 mutations. Thus, we first established hTERT-immortalized proximal cyst cells with somatic PKD1 mutations. Through transcriptome sequencing and Gene Ontology (GO) analysis, we found that upregulated genes were related to cell division and that downregulated genes were related to cell differentiation. We wondered whether the upregulated gene for the chemokine CXCL12 is related to the mTOR signaling pathway in cyst growth in ADPKD. CXCL12 mRNA expression and secretion were increased in RC cell lines. We then examined CXCL12 levels in RC fluids from patients with ADPKD and found increased CXCL12 levels. The CXCL12 receptor CXC chemokine receptor 4 (CXCR4) was upregulated, and the mTOR signaling pathway, which is downstream of the CXCL12/CXCR4 axis, was activated in ADPKD kidney tissue. To confirm activation of the mTOR signaling pathway by CXCL12 via CXCR4, we treated the RC cell lines with recombinant CXCL12 and the CXCR4 antagonist AMD3100; CXCL12 induced the mTOR signaling pathway, but the CXCR4 antagonist AMD3100 blocked the mTOR signaling pathway. Taken together, these results suggest that enhanced CXCL12 in RC fluids activates the mTOR signaling pathway via CXCR4 in ADPKD cyst growth.

• Tuberculosis and Respiratory Diseases
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• 제79권4호
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• pp.248-256
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• 2016

Somatic mutations that lead to hyperactivation of epidermal growth factor receptor (EGFR) signaling are detected in approximately 50% of lung adenocarcinoma in people from the Far East population and tyrosine kinase inhibitors are now the standard first line treatment for advanced disease. They have led to a doubling of progression-free survival and an increase in overall survival by more than 2 years. However, emergence of resistant clones has become the primary cause for treatment failure, and has created a new challenge in the daily management of patients with EGFR mutations. Identification of mechanisms leading to inhibitor resistance has led to new therapeutic modalities, some of which have now been adapted for patients with unsuccessful tyrosine kinase inhibitor treatment. In this review, we describe mechanisms of tyrosine kinase inhibitor resistance and the available strategies to overcoming resistance.

• Asian Pacific Journal of Cancer Prevention
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• 제16권14호
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• pp.5619-5624
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• 2015

Pancreatic cancer is a fatal malignancies which is predominantly seen in men and at advanced age (40-85 years) and has an aggressive course. Its frequency is gradually increasing over the past years. It accounts for 2% of all cancers and 5% of cancer-related deaths. Pancreatic cancer takes the first place among asymptomatic cancers. Ninety percent of cases are adenocarcinomas. Ten percent of the patients have a familial disposition. The disease is very difficult to detect as it has no early signs and spreads rapidly to surrounding organs is one of the most deadly types of cancer. Pancreatic cancer may result from hereditary germline or somatic acquired mutations in cancer-related genes and mutations also cause cancer progression and metastasis.

• Genomics & Informatics
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• 제17권3호
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• pp.23.1-23.6
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• 2019

The acquisition of somatic mutations is the most common event in cancer. Neoantigens expressed from genes with mutations acquired during carcinogenesis can be tumor-specific. Since the immune system recognizes tumor-specific peptides, they are potential targets for personalized neoantigen-based immunotherapy. However, the discovery of druggable neoantigens remains challenging, suggesting that a deeper understanding of the mechanism of neoantigen generation and better strategies to identify them will be required to realize the promise of neoantigen-based immunotherapy. Alternative splicing and RNA editing events are emerging mechanisms leading to neoantigen production. In this review, we outline recent work involving the large-scale screening of neoantigens produced by alternative splicing and RNA editing. We also describe strategies to predict and validate neoantigens from RNA sequencing data.

• Molecules and Cells
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• 제42권6호
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• pp.441-447
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• 2019

RAS gene mutations are frequently found in one third of human cancers. Affecting approximately 1 in 1,000 newborns, germline and somatic gain-of-function mutations in the components of RAS/mitogen-activated protein kinase (RAS/MAPK) pathway has been shown to cause developmental disorders, known as RASopathies. Since RAS-MAPK pathway plays essential roles in proliferation, differentiation and migration involving developmental processes, individuals with RASopathies show abnormalities in various organ systems including central nervous system. The frequently seen neurological defects are developmental delay, macrocephaly, seizures, neurocognitive deficits, and structural malformations. Some of the defects stemmed from dysregulation of molecular and cellular processes affecting early neurodevelopmental processes. In this review, we will discuss the implications of RAS-MAPK pathway components in neurodevelopmental processes and pathogenesis of RASopathies.

• Genomics & Informatics
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• 제21권1호
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• pp.11.1-11.5
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• 2023

Breast cancer is the most common cancer worldwide, and advanced breast cancer with metastases is incurable mainly with currently available therapies. Therefore, it is essential to understand molecular characteristics during the progression of breast carcinogenesis. Here, we report a dataset of whole genomes from the human mammary epithelial cell system derived from a reduction mammoplasty specimen. This system comprises pre-stasis 184D cells, considered normal, and seven cell lines along cancer progression series that are immortalized or additionally acquired anchorage-independent growth. Our analysis of the whole-genome sequencing (WGS) data indicates that those seven cancer progression series cells have somatic mutations whose number ranges from 8,393 to 39,564 (with an average of 30,591) compared to 184D cells. These WGS data and our mutation analysis will provide helpful information to identify driver mutations and elucidate molecular mechanisms for breast carcinogenesis.