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)

The stem cell factor/c-kit tyrosine kinase receptor pathway has been shown to be important for tumor growth and progression in several cancers, including mast cell diseases, gastrointestinal stromal tumor, acute myeloid leukemia, small cell lung carcinoma, and Ewing sarcoma. Studies using the oral agent STI-571 (Gleevec, Novartis), an inhibitor of the tyrosine kinases bcr-abl, c-kit, and PDGFR, have shown significant responses in patients with chronic myelogenous leukemia and gastrointestinal stromal tumor. With the aim of identifying additional groups of tumors that may use the stem cell factor/c-kit pathway and secondarily may be responsive to STI-571 treatment, this study surveyed 151 primary tumors from patients treated at St. Jude Children's Research Hospital for immunohistochemical expression of c-kit. Formalin-fixed, paraffin-embedded sections were stained with rabbit polyclonal anti-human c-kit (CD117, Dako) using standard avidin-biotin-peroxidase complex technique, antigen retrieval, and an automated stainer. Strong, diffuse staining for c-kit was seen in a proportion of synovial sarcomas, osteosarcomas, and Ewing sarcomas. Strong, diffuse staining was less common in neuroblastomas, Wilms' tumors, and rhabdomyosarcomas and was negative in alveolar soft part sarcomas and desmoplastic small round cell tumors. Tumors with strong, diffuse staining for c-kit in a pattern similar to gastrointestinal stromal tumor may represent suitable targets for new therapeutic agents.
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PMID:C-kit expression in pediatric solid tumors: a comparative immunohistochemical study. 1191 27

Abnormalities of chromosome 2p23 with expression of ALK1 and p80 occur in both inflammatory myofibroblastic tumor (IMT) and anaplastic large cell lymphoma. This immunohistochemical study investigates whether the ALK family of neoplasms includes fibroblastic-myofibroblastic, myogenic, and spindle cell tumors. Formalin-fixed paraffin-embedded archival tissues from 10 IMTs and 125 other soft tissue tumors were stained for ALK1 and p80 with standard immunohistochemistry. ALK1 and/or p80 reactivity was observed in a cytoplasmic pattern in IMT (4/10; 40%), malignant peripheral nerve sheath tumor (4/10; 40%), rhabdomyosarcoma (6/31; 19%), leiomyosarcoma (1/10; 10%), and malignant fibrous histiocytoma (1/11; 9%). No staining was observed in nodular fasciitis, desmoid, infantile myofibromatosis, infantile fibrosarcoma, synovial sarcoma, leiomyoma, or myofibrosarcoma. Alveolar rhabdomyosarcomas (4/16; 25%) displayed a distinctive dot-like cytoplasmic positivity. No cases displayed nuclear reactivity. Fluorescent in situ hybridization on 12 of the positive cases revealed a combination of abnormalities including ALK break-apart signals, nucleophosmin (NPM)/ALK fusions, or extra copies of 2p23. This study demonstrates that in addition to IMT, abnormalities of ALK1 and p80 expression with a variety of structural chromosomal changes are found in several sarcomas, especially rhabdomyosarcoma and malignant peripheral nerve sheath tumor. Although immunoreactivity in non-IMTs cannot distinguish between structural abnormalities involving 2p23 or additional copies of 2p23, it supports the concept of ALK involvement in a larger group of neoplasms, some of which have other documented clonal abnormalities. In IMT, immunohistochemistry for ALK1 and p80 is useful as an indicator of a 2p23 abnormality, but it must be interpreted in the context of histologic and other clinicopathologic data if used as an adjunct to differential diagnosis.
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PMID:Expression of ALK1 and p80 in inflammatory myofibroblastic tumor and its mesenchymal mimics: a study of 135 cases. 1221 10

HER-2/Neu overexpression is seen in 20% to 30% of invasive breast carcinomas and has been reported in as many as 80% of high-grade infiltrating carcinomas. Earlier studies have suggested that 100% of the tumor cells in mammary Paget disease show overexpression of HER-2 protein. We undertook this study to assess HER-2 status of mammary Paget disease and of the underlying breast carcinoma, when present, by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Formalin-fixed, paraffin-embedded tissue from 20 cases of mammary Paget disease were analyzed for HER-2 status by IHC and FISH. IHC for estrogen receptor (ER) was also performed. The patients ranged in age from 34 to 88 years, with a mean age of 62 years. Eighty percent of the cases showed strong overexpression (3+) of HER-2 protein by IHC, and all of these cases showed more than 5-fold amplification of the HER-2 gene by FISH. The remaining 4 cases, which were negative for HER-2/Neu by IHC, showed no amplification by FISH. All of the latter cases expressed ER, whereas no case that overexpressed HER-2 expressed ER. Sixteen cases had an underlying tumor, which was in situ in 6 cases. The underlying tumors were identical to the Paget disease with respect to their HER-2/Neu overexpression by both IHC and FISH. HER-2 overexpression was identified in 80% of our cases of Paget disease. There was 100% concordance between HER-2 protein overexpression by immunohistochemistry and gene amplification in both the Paget and the underlying tumor. Moreover, all of the cases negative for HER-2 overexpression expressed ER, whereas those positive for HER-2 did not.
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PMID:Assessment of Her-2/Neu status by immunohistochemistry and fluorescence in situ hybridization in mammary Paget disease and underlying carcinoma. 1277 94

Major prognostic factors for early-stage non-small-cell lung cancer (NSCLC) are tumor size and nodal status. It has been suggested that HER2/neu overexpression may be related to poor prognosis in NSCLC. We evaluated the significance of HER2/neu overexpression on survival in patients with NSCLC. Data were collected on 239 patients treated surgically for stage I/II NSCLC between 1987 and 1996. None of the patients received adjuvant chemotherapy or radiation. Formalin-fixed, paraffin-embedded tumor tissue samples were stained with p185/HER2 receptor antibody. Results were reported as positive (2+, 3+) or negative (0, 1+) (Group A). A separate analysis considered only 3+ as positive (Group B). HER2/neu overexpression was seen in 18% in Group A (43 of 239) and 6% in Group B (15 of 239). HER2/neu overexpression was highest in bronchoalveolar cell carcinoma and adenocarcinoma. More stage I tumors were positive than stage II in both groups, but this was significant only in Group A (21% vs. 7%, P = 0.02). No difference was seen with age, gender, or grade for either group. In Group A, the relapse rate was 55% for HER2/neu-overexpressing tumors and 31% for HER2/neu-negative tumors (P = 0.003). Median time to relapse in patients with HER2/neu-positive tumors was 2.9 years; it was not reached in patients with HER2/neu-negative tumors. Median survival of patients with HER2/neu-positive tumors was 3.6 years compared to 5 years in patients with HER2/neu-negative tumors (P = 0.66). In Group B, the relapse rate was 60% for HER2/neu-overexpressing tumors and 33% for negative tumors (P = 0.036). Median time to relapse was 3.4 years in HER2/neu positive and had not been reached in negative tumors. There was no difference in 5-year survival rates for both groups (47% for HER2/neu positive and 50% for negative, P = 0.66).
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PMID:Effect of HER2/neu expression on survival in non-small-cell lung cancer. 1470 Apr 81

Gastrointestinal stromal tumors (GISTs) are KIT expressing spindle cell, epithelioid and rarely pleomorphic mesenchymal tumors. The majority of GISTs show gain-of-function KIT mutations. However, GISTs without KIT mutations and GISTs with weak or lack of immunohistochemical KIT expression have also been reported. Recently, gain-of-function mutations in exon 18 (activation loop) and exon 12 (juxtamembrane domain) of the PDGFRA were identified in such tumors. The purpose of this study was to test the hypothesis that PDGFRA mutation may define a specific clinicopathologic subgroup of GISTs. A total of 447 KIT exon 11 (juxtamembrane domain) mutation-negative GISTs were studied. DNA samples were obtained from formaldehyde-fixed paraffin-embedded tissues. Genomic sequences of PDGFRA exons 18 and 12 were evaluated for the mutations by PCR amplification and direct sequencing. PDGFRA exon 18 mutations were identified in 122 of 346 (35.3%) gastric GISTs and two of 75 (2.7%) intestinal GISTs. A great majority of these mutations represented simple T to A missense mutation at the codon 842 leading to substitution of the valine for aspartic acid (D842 V). However, in-frame deletions and deletions with point mutations clustering between codons 841-847 were found in approximately 23% of all exon 18 mutations. Mutations in PDGFRA exon 12 were found only in 10 of 170 (5.8%) gastric and one of 54 (1.9%) intestinal GISTs negative for KIT exon 11 and PDGFRA exon 18 mutations. There were seven substitutions of aspartic acid for valine at codon 561 (V561D) and four in-frame deletions with point mutations clustering between codons 566 and 571. The majority of GISTs with PDGFRA mutations had pure or predominant epithelioid morphology. Low mitotic activity, < or =5 mitoses/50HPF was detected in 81% of analyzed GISTs including larger, >5 cm tumors. Based on long-term follow-up (average 135 months), a majority (83.5%) of GISTs with PDGFRA mutations followed a benign course.
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PMID:A great majority of GISTs with PDGFRA mutations represent gastric tumors of low or no malignant potential. 1514 65

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin that is associated with a high incidence of recurrence and metastasis. The therapeutic arsenal for this malignancy is limited and once it spreads, there is no effective treatment. c-kit expression has been demonstrated previously in primary MCCs thus raising the possibility of treating MCCs with imatinib mesylate, the tyrosine kinase inhibitor that has shown promise in the management of c-kit expressing tumors. In this study we examine 25 additional primary MCCs and also 6 of their lymph node metastases. Formalin-fixed, paraffin-embedded tissues were stained immunohistochemically with an antibody directed against the KIT receptor. Percentage and intensity of staining were analyzed semiquantitatively using a three-tiered system. Twenty-one of the 25 (84%) primary tumors stained positively for KIT, of which 14 (67%) showed widespread positivity. Five of the 6 lymph nodes (83%) were similarly positive. High mitotic rate and vascular invasion in the primary tumors tended to be associated with prominent staining in the lymph node metastases. No association was found between c-kit expression and outcome. We confirm that the majority of primary MCCs express c-kit and further find that metastases are positive for the KIT receptor as well. Thus, c-kit expression may be an early event in the transformation of MCC, but not a marker for tumor progression.
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PMID:c-kit expression in primary and metastatic merkel cell carcinoma. 1561 26

Formaldehyde is a highly toxic chemical common in industrial effluents, and it is also an intermediate in bacterial metabolism of one-carbon growth substrates, although its role as a bacterial growth substrate per se has not been extensively reported. This study investigated two highly formaldehyde-resistant formaldehyde utilizers, strains BIP and ROS1; the former strain has been used for industrial remediation of formaldehyde-containing effluents. The two strains were shown by means of 16S rRNA characterization to be closely related members of the genus Methylobacterium. Both strains were able to use formaldehyde, methanol and a range of multicarbon compounds as their principal growth substrate. Growth on formaldehyde was possible up to a concentration of at least 58 mM, and survival at up to 100 mM was possible after stepwise acclimatization by growth at increasing concentrations of formaldehyde. At such high concentrations of formaldehyde, the cultures underwent a period of formaldehyde removal without growth before the formaldehyde concentration fell below 60 mM, and growth could resume. Two-dimensional electrophoresis and MS characterization of formaldehyde-induced proteins in strain BIP revealed that the pathways of formaldehyde metabolism, and adaptations to methylotrophic growth, were very similar to those seen in the well-characterized methanol-utilizing methylotroph Methylobacterium extorquens AM1. Thus, it appears that many of the changes in protein expression that allow strain BIP to grow using high formaldehyde concentrations are associated with expression of the same enzymes used by M. extorquens AM1 to process formaldehyde as a metabolic intermediate during growth on methanol.
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PMID:Adaptation and acclimatization to formaldehyde in methylotrophs capable of high-concentration formaldehyde detoxification. 1607 40

KIT is expressed in most gastrointestinal stromal tumors, and they usually show c-kit aberrations (most frequently deletions or deletions coexisting with a single or multiple point mutations). Recently, several studies regarding KIT expression in gynecologic tumors have been reported; however, their outcomes were not consistent. In this study, we immunohistochemically examined KIT expression in sarcomas of the female genital tract and studied the existence of c-kit aberrations to elucidate the characteristics of KIT-positive tumors in the gynecologic region. Formalin-fixed, paraffin-embedded tissues from 25 surgically resected and 1 biopsy specimen from 26 patients were used. Histological diagnoses included 14 uterine leiomyosarcomas, 6 carcinosarcomas, 5 endometrial stromal sarcomas, and 1 vaginal epithelioid sarcoma. Immunohistochemical studies were performed using anti-KIT polyclonal antibody. Only four of the above tumors (15%) were positive for KIT, all of which were carcinosarcomas. Specific KIT immunoreactivity was observed in the only carcinomatous components in one case, in the only sarcomatous component in two cases, and in the both components in one case. However, none of the cases showed c-kit aberrations in exons 9, 11, 13, and 17. Judicious decision is mandatory before applying Imatinib therapy to KIT-positive gynecologic tumors.
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PMID:Immunohistochemical evaluation of KIT expression in sarcomas of the gynecologic region. 1630 88

The HER2/neu oncogene has been reported to be amplified in > 20% of invasive ductal carcinomas. In order to investigate the HER2/neu status in pure populations of breast cancer cells, a laser capture microdissection (LCM) system was used. Formalin-fixed paraffin-embedded breast tissue areas corresponding to normal ducts, ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC) were microdissected and genomic DNA was isolated by a modified proteinase K- phenol extraction method and subjected to PCR for HER2/neu analysis. One hundred % concordance for detection of the HER2/neu gene amplification was found between immunohistochemistry and PCR used in combination with LCM. Our results indicated that LCM is a powerful technique for isolating pure populations of cells from paraffin-embedded tissue sections and that these cells can be used to study genomic alterations at the DNA level.
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PMID:Analysis of the HER2/neu gene amplification in microdissected breast cancer tumour samples. 1661 88

Hepatocyte growth factor (HGF)-MET signalling in cancer biology has been well characterized in multiple organ systems. Numerous investigations have described an up-regulation of c-met mRNA in human colorectal adenomas and carcinomas. However, a quantitative immunohistochemical analysis of MET and HGF protein levels in tumor tissues has not been reported previously. Formalin-fixed and paraffin-embedded tissues from 41 colorectal adenomas and 49 colorectal carcinomas were characterized by immunofluorescent staining using HGF- and MET-specific antibodies. The immunoreactivity was evaluated by confocal laser scanning microscopy, computer-based image analysis and appropriate statistical tests. Normal colorectal mucosa, adenomas and carcinomas exhibited comparable levels of MET and HGF proteins. MET expression in carcinomas, although statistically not significant, demonstrated a tendency to correlate with the grade of differentiation. Correlations of MET and HGF with other clinico-pathological variables including the extent of the mucinous component and the pTNM stage were not observed. The ratio of HGF in carcinoma vs. non-neoplastic tissue was significantly different between high and low carcinoma stage. Alterations of absolute levels of MET and HGF protein during the colorectal adenoma-carcinoma sequence were not significant. The presumed role of MET-HGF interactions in large bowel carcinogenesis may therefore be a result of or depend upon other regulatory factors involved in MET-mediated signalling pathways.
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PMID:Quantification of MET and hepatocyte growth factor/scatter factor expression in colorectal adenomas, carcinomas and non-neoplastic epithelia by quantitative laser scanning microscopy. 1754 22


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