Molecular diagnosis of pancreas carcinoma

Chu, T. Ming

doi:10.1002/(sici)1098-2825(1997)11:4<225::aid-jcla9>3.0.co;2-7

Cited by 19 publications

(9 citation statements)

References 58 publications

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“…We did not find these alterations in normal counterparts of the SNU-324 cell line. The defects of MSI and mismatch repair genes suggest the possibility of new mutator phenotype for pancreatic carcinogenesis, as described previously (Chu 1997). These wellcharacterized pancreatic carcinoma cell lines will be useful tools for investigating the biological characteristics of pancreatic cancer, particularly those related to the roles of MSI, mismatch repair genes, and genetic alterations in TGFBR2 in cellular transformation.…”

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of four human pancreatic carcinoma cell lines

Yoon

Kim

et al. 2002

Cell and Tissue Research

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We characterized four pancreatic carcinoma cell lines (designated SNU-213, SNU-324, SNU-410, and SNU-494) established from histopathologically varied primary or liver metastatic tumor samples of Korean patients. Three cell lines grew as adherent monolayers and one as adherent and floating cell clumps. All lines had: (1) relatively high viability; (2) an absence of mycoplasma or bacterial contamination; (3) genetic heterogeneity as assessed by DNA-fingerprinting analysis; (4) an absence of MADH4 mutation. Among the lines, three lines had mutations in codon 12 in K- ras, two lines harbored p53 mutations within the DNA-binding domain; two lines had homozygous deletions in both p16 and p15 genes; and one line had a missense mutation. Two lines (SNU-324 and SNU-410) had genetic alterations in the TGFBR2 gene: the SNU-324 line had a -1-bp or +1-bp mutation in 10-bp polydeoxyadenine repeat tracts; the SNU-410 line had a genomic deletion in this gene. Mutation analysis of mismatch repair genes demonstrated that SNU-324 has two heterozygous missense mutations in different exons of the hMLH1 gene. In addition, this line showed microsatellite instability and harbored frameshift mutations in simple repeated sequences of the coding regions of the TGFBR2, BAX, and hMSH3 genes. These defects of microsatellite instability and mismatch repair genes suggest the possibility of a new mutator phenotype for pancreatic carcinogenesis. These cell lines should be very useful for studying the biology of pancreatic carcinoma, particularly those related to mutator phenotype and genetic alterations in the TGFBR2 gene.

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Section: Discussionmentioning

confidence: 99%

Establishment and characterization of four human pancreatic carcinoma cell lines

Yoon

Kim

et al. 2002

Cell and Tissue Research

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“…However, PDA exhibits a range of genetic alterations some of which could be amenable to targeted therapy. One of these alterations is the genetic loss or epigenetic silencing of the CDKN2A tumor suppressor [5-8]. …”

Section: Introductionmentioning

confidence: 99%

CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer

2014

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Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, in part, due to the therapy-recalcitrant nature of the disease. Loss of the CDK4/6 inhibitor CDKN2A is a signature genetic event in PDA. Therefore, PDA may be amenable to treatment with pharmaceutical CDK4/6 inhibitors. Surprisingly, response to CDK4/6 inhibition was highly variable in PDA models, and associated with differential suppression of gene expression. Mitotic genes were repressed and FOXM1 was uniformly attenuated; however, genes involved in DNA replication were uniquely suppressed in sensitive models. Aberrant induction of Cyclin E1 was associated with resistance, and knockdown demonstrated synergistic suppression of the cell cycle with CDK4/6 inhibition. Combination therapies are likely required for the effective treatment of disease, and drug screening demonstrated additive/antagonistic interactions with CDK4/6 inhibitors. Agents dependent on mitotic progression (taxanes/PLK1 inhibitors) were antagonized by CDK4/6 inhibition, while the response to 5-FU and gemcitabine exhibited drug specific interactions. PI3K/MTOR and MEK inhibitors potently cooperated with CDK4/6 inhibition. These agents were synergistic with CDK4/6 inhibition, blocked the aberrant upregulation of Cyclin E1, and yielded potent inhibition of tumor cell growth. Together, these data identify novel mechanisms of resistance to CDK4/6 inhibitions and provide a roadmap for combination therapies in the treatment of PDA.

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“…This led to the ®nal identi®cation of DPC4, which is now believed to be involved in more than 50% of pancreatic carcinomas. DPC4 is highly homologous to mad, and displays frequent mutations in its carboxy terminus which may induce transcriptional activtion (Chu, 1997;Frank et al, 1997;Lagna et al, 1996;Moskaluk and Kern, 1996).…”

Section: Neuroectodermal Tumors and Hedgehog Signallingmentioning

confidence: 52%

Transgenic mice as research tools in neurocarcinogenesis

Rovigatti¹,

Afanasyeva²,

Brandner³

et al. 1998

J Neurovirol

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Transgenic animal models for neurocarcinogenesis have provided signi®cant insights into the molecular mechanisms underlying carcinogenic processes, including those which affect the nervous system. In view of the very rapid pace of acquisition of knowledge, it is not possible to cover all transgenic mouse models for neural tumors. Instead, this article discusses some of the most important technical innovations for manipulation of the mammalian genome (notably the various methods for targeted genome modi®cations, as well as the technology for introducing large DNA fragments into the germ line of mice), and presents a selection of the transgenic mouse models which are proving most promising for furthering our understanding of the pathogenetic basis of cancer in the nervous system.

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Molecular diagnosis of pancreas carcinoma

Cited by 19 publications

References 58 publications

Establishment and characterization of four human pancreatic carcinoma cell lines

Establishment and characterization of four human pancreatic carcinoma cell lines

CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer

Transgenic mice as research tools in neurocarcinogenesis

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