Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

More complete knowledge of the molecular mechanisms underlying cancer will improve prevention, diagnosis and treatment. Efforts such as The Cancer Genome Atlas are systematically characterizing the structural basis of cancer, by identifying the genomic mutations associated with each cancer type. A powerful complementary approach is to systematically characterize the functional basis of cancer, by identifying the genes essential for growth and related phenotypes in different cancer cells. Such information would be particularly valuable for identifying potential drug targets. Here, we report the development of an efficient, robust approach to perform genome-scale pooled shRNA screens for both positive and negative selection and its application to systematically identify cell essential genes in 12 cancer cell lines. By integrating these functional data with comprehensive genetic analyses of primary human tumors, we identified known and putative oncogenes such as EGFR, KRAS, MYC, BCR-ABL, MYB, CRKL, and CDK4 that are essential for cancer cell proliferation and also altered in human cancers. We further used this approach to identify genes involved in the response of cancer cells to tumoricidal agents and found 4 genes required for the response of CML cells to imatinib treatment: PTPN1, NF1, SMARCB1, and SMARCE1, and 5 regulators of the response to FAS activation, FAS, FADD, CASP8, ARID1A and CBX1. Broad application of this highly parallel genetic screening strategy will not only facilitate the rapid identification of genes that drive the malignant state and its response to therapeutics but will also enable the discovery of genes that participate in any biological process.
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PMID:Highly parallel identification of essential genes in cancer cells. 1909 43

Breast cancer is the most common malignancy in women in the Western world. Except for the high breast cancer risk in BRCA1 and BRCA2 mutation carriers as well as the risk for breast cancer in certain rare syndromes caused by mutations in TP53, STK11, PTEN, CDH1, NF1 or NBN, familial clustering of breast cancer remains largely unexplained. Despite significant efforts, BRCA3 could not be identified, but several reports have recently been published on genes involved in DNA repair and single nucleotide polymorphisms (SNPs) associated with an increased breast cancer risk. Although candidate gene approaches demonstrated moderately increased breast cancer risks for rare mutations in genes involved in DNA repair (ATM, CHEK2, BRIP1, PALB2 and RAD50), genome-wide association studies identified several SNPs as low-penetrance breast cancer susceptibility polymorphisms within genes as well as in chromosomal loci with no known genes (FGFR2, TOX3, LSP1, MAP3K1, TGFB1, 2q35 and 8q). Some of these low-penetrance breast cancer susceptibility polymorphisms also act as modifier genes in BRCA1/BRCA2 mutation carriers. This review not only outlines the recent key developments and potential clinical benefit for preventive management and therapy but also discusses the current limitations of genetic testing of variants associated with intermediate and low breast cancer risk.
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PMID:Breast cancer susceptibility: current knowledge and implications for genetic counselling. 1909 72

Neurofibromatosis type 1 or Recklinghausen disease is one of the most common hereditary autosomal dominant diseases. The disease-causing gene can be found on chromosome 17 as an NF1 tumor suppressor gene. The mutation of this gene leads to the loss of tumor suppressor function, which in turn causes the development of benign and malignant tumors. In 25% of the cases gastrointestinal manifestations are found, most often GIST. The close correlation of the two diseases are well known in the literature, there are more than 160 published cases. GIST develops in 7% of patients with neurofibromatosis, and among these patients the occurrence of NF1 is 150-180 times more frequent than in the general population. Neurofibromatosis associated with GIST is a different entity and, unlike sporadic GIST, it is usually multiplex and almost always develops in the small bowel. There is a slightly higher incidence among women than in men, and the disease develops at young age. Histological characteristics include spindle cell type, skeinoid fibers and frequent S100 positivity. Low mitotic activity usually suggests better prognosis. c-KIT and PDGFRA mutation is very rare, in agreement with the hypothesis that the pathogenesis of NF1-GIST is not c-KIT dependent. It is presumed that neurofibromatosis associated and sporadic GIST have different pathogenesis, and that the development of GIST tumor in neurofibromatosis is part of the hereditary disease. c-KIT and PDGFRA mutations--as shown in a few known cases--probably develop at a later step of tumor genesis. Imatinib, which has revolutionized the therapy of GIST, cannot be used in this patient group, however, as of today not enough information is available.
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PMID:[Gastrointestinal stromal tumors in neurofibromatosis type 1]. 1914 98

Malignant peripheral nerve sheath tumors (MPNSTs) develop in patients with underlying NF1, and usually arise as a result of malignant transformation of a pre-existing plexiform neurofibroma. The clonal cytogenetic abnormalities reported in primary MPNST include complex karyotypes with chromosome numbers in the triploid or tetraploid range with recurrent abnormalities of several chromosomes including losses or imbalances. As a prelude to cell biological, pharmacological, and functional studies to investigate pathways and gene(s) associated with multistep tumorigenesis, which includes progression, metastasis and resistance to therapy in MPNST, detailed molecular cytogenetic and genetic analyses of cell lines from primary, metastatic and recurrent MPNST with underlying NF1 disorder have been performed. The clonal cytogenetic abnormalities detected in the primary tumor cell line were similar to those observed in primary cultures of this tumor. Due to the complexity of the rearrangements seen by G-banded karyotype analysis, further characterization of the clonal abnormalities in these three cell lines was performed by molecular cytogenetic techniques, including CGH and SKY. CGH analysis detected recurrent deletions of 9p, 12q21-q32, complete losses of the X-chromosome, and gains of the chromosomal segment 17q25 in all three cell lines. SKY analysis detected extensive clonal abnormalities in these cell lines. The nature and the alterations of the cell cycle regulators, particularly those associated with G1-S checkpoints and known to be deregulated in MPNST, were studied. These cell cycle regulators included those associated with Rb1-cyclin D1 and the p53 pathways. The findings are consistent with the argument that an imbalance between the cyclin activators of CDKs and inhibitory proteins such as p16 result in uncontrollable proliferation in the cell lines, associated with progression of the disease. LOH and expression of the p53 gene in metastatic and recurrent cell lines was observed, as reported by others. The role of biallelic inactivation of p53 gene in MPNST with underlying NF1 mutations, however, needs further study. Overexpression of Rb1-protein observed in metastatic and recurrent cell lines is indicative of its role in the progression of the disease. One of the most important observations of this study is that Nm23-H1 expression is closely associated with advanced or metastatic disease. In summary, MPNST cell lines derived from a patient with metastatic and recurrent disease with NF1 disorder were characterized and a gene associated with metastatic potential which is amenable to therapeutic and chemo-preventative approaches was identified. These cell lines with extensive characterization of genetic abnormalities are likely to provide important reagents for biochemical, molecular and pharmacological studies related to MPNST.
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PMID:Molecular characterization of permanent cell lines from primary, metastatic and recurrent malignant peripheral nerve sheath tumors (MPNST) with underlying neurofibromatosis-1. 1941 72

Glioblastoma is the most common and highest-grade brain tumor, causing over 10,000 deaths each year in the US alone. Given the resistance of this tumor to standard surgery, radiation and chemotherapy, an understanding of the underlying genetic lesions is vital. Recent efforts to comprehensively profile glioblastomas using the latest technologies, both by The Cancer Genome Atlas (TCGA) project and by other groups, are addressing this need. Some genetic aberrations in glioblastoma have been known for decades, but early output from the new profiling initiatives has further illuminated the relevant genetics in this disease. Some genetic lesions, such as TP53 mutation, NF1 deletion or mutation, and ERBB2 amplification, have been found to be more common than was previously reported. New and unexpected discoveries have also been made, such as frequent mutations of the IDH1 and IDH2 genes in secondary glioblastoma. We might be tempted to speculate that we are approaching a comprehensive knowledge of the genetic lesions involved in glioblastoma, although other major discoveries doubtless remain to be made. In addition, the complex task of incorporating our updated knowledge into new--and possibly personalized--therapies for patients with glioblastoma still lies ahead.
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PMID:Advances in the genetics of glioblastoma: are we reaching critical mass? 1959 14

The Warburg effect describes how cancer cells down-regulate their aerobic respiration and preferentially use glycolysis to generate energy. To evaluate the link between hypoxia and Warburg effect, we studied mitochondrial electron transport, angiogenesis and glycolysis in pheochromocytomas induced by germ-line mutations in VHL, RET, NF1 and SDH genes. SDH and VHL gene mutations have been shown to lead to the activation of hypoxic response, even in normoxic conditions, a process now referred to as pseudohypoxia. We observed a decrease in electron transport protein expression and activity, associated with increased angiogenesis in SDH- and VHL-related, pseudohypoxic tumors, while stimulation of glycolysis was solely observed in VHL tumors. Moreover, microarray analyses revealed that expression of genes involved in these metabolic pathways is an efficient tool for classification of pheochromocytomas in accordance with the predisposition gene mutated. Our data suggest an unexpected association between pseudohypoxia and loss of p53, which leads to a distinct Warburg effect in VHL-related pheochromocytomas.
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PMID:The Warburg effect is genetically determined in inherited pheochromocytomas. 1976 84

Malignant peripheral nerve sheath tumor (MPNST) is a rare soft tissue sarcoma. We established a new human MPNST cell line (designated FMS-1) from MPNST of the right brachial plexus of a 69-year-old woman with NF1. The cell line has been maintained for >24 months with >100 passages. FMS-1 cells showed a fibrosarcoma-like or epithelioid pattern in the heterotransplanted tumor, compared with a fascicular growth pattern of short-spindle tumor cells in the primary tumor. Immunophenotypically, FMS-1 cells showed almost the same characteristics as the primary tumor. Cytogenetic and molecular analyses revealed a deletion in exons 5-8 of the p53 gene. Epidermal growth factor receptor (EGFR) and cyclooxygenase (COX)-2 were expressed in FMS-1 cells. To improve the highly aggressive course and poor prognosis and establish new therapeutic methods, molecular genetic and biological characterizations of MPNST are required. Thus, FMS-1 cells might be useful for investigating biological behaviors and developing new molecular-targeting antitumor drugs for MPNST expressing EGFR or COX-2.
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PMID:Establishment and characterization of a novel human malignant peripheral nerve sheath tumor cell line, FMS-1, that overexpresses epidermal growth factor receptor and cyclooxygenase-2. 1992 Dec 53

Gastrointestinal stromal tumors (GISTs) may be sporadic or inherited. Although KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic and inherited GISTs, a small subset of GISTs are negative for both. Besides the classical Familial GIST Syndrome, GIST can occur as part of multi-neoplastic disease. The present study was designed to analyze the synchronous and metachronous tumors developed among GIST patients assessed by our institution for GIST Syndrome setting recognition. Patients (n=141) with primary GIST (77 men and 64 women) were recruited between 1988 and 2007 and their clinical and pathological records were reviewed. Mutation analysis of KIT, PDGFRA, NF1 and MMR genes was performed on somatic and peripheral blood DNA. GISTs occurred associated with other primary malignancies in 46 of 141 (32.6%) patients. The most common neoplasms were gastrointestinal and genitourinary. A novel exon 6 germline large deletion of NF1 was identified in the NF1/GIST kindred. The development of GIST associated with other neoplasms is common and diagnosis of peculiar benign associated-neoplasms warrants the search for familial cancer susceptibility. In particular, syndromic or familial settings have to be suspected in the presence of neurofibroma or lung chordoma in C-KIT and PDGFRA negative GIST patients.
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PMID:Gastrointestinal stromal tumor and other primary metachronous or synchronous neoplasms as a suspicion criterion for syndromic setting. 2004 5

The Cancer Genome Atlas Network recently cataloged recurrent genomic abnormalities in glioblastoma multiforme (GBM). We describe a robust gene expression-based molecular classification of GBM into Proneural, Neural, Classical, and Mesenchymal subtypes and integrate multidimensional genomic data to establish patterns of somatic mutations and DNA copy number. Aberrations and gene expression of EGFR, NF1, and PDGFRA/IDH1 each define the Classical, Mesenchymal, and Proneural subtypes, respectively. Gene signatures of normal brain cell types show a strong relationship between subtypes and different neural lineages. Additionally, response to aggressive therapy differs by subtype, with the greatest benefit in the Classical subtype and no benefit in the Proneural subtype. We provide a framework that unifies transcriptomic and genomic dimensions for GBM molecular stratification with important implications for future studies.
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PMID:Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. 2012 51

Up to 30% of pheochromocytomas and paragangliomas are associated with germline RET, Von Hippel-Lindau (VHL), neurofibromatosis type I (NF1), and succinate dehydrogenase subunits (SDHB, SDHC, and SDHD) mutations. Genetic testing allows familial counseling and identifies subjects at high risk of malignancy (SDHB mutations) or significant multiorgan disease (RET, VHL, or NF1). However, conventional genetic testing for all loci is burdensome and costly. We performed immunohistochemistry for SDHB on 58 tumors with known SDH mutation status. We defined positive as granular cytoplasmic staining (a mitochondrial pattern), weak diffuse as a cytoplasmic blush lacking definite granularity, and negative as completely absent staining in the presence of an internal positive control. All 12 SDH mutated tumors (6 SDHB, 5 SDHD, and 1 SDHC) showed weak diffuse or negative staining. Nine of 10 tumors with known mutations of VHL, RET, or NF1 showed positive staining. One VHL associated tumor showed weak diffuse staining. Of 36 tumors without germline mutations, 34 showed positive staining. One paraganglioma with no known SDH mutation but clinical features suggesting familial disease was negative, and one showed weak diffuse staining. We also performed immunohistochemistry for SDHB on 143 consecutive unselected tumors of which 21 were weak diffuse or negative. As SDH mutations are virtually always germline, we conclude that approximately 15% of all pheochromocytomas or paragangliomas are associated with germline SDH mutation and that immunohistochemistry can be used to triage genetic testing. Completely absent staining is more commonly found with SDHB mutation, whereas weak diffuse staining often occurs with SDHD mutation.
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PMID:Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. 2023 88


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