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)

Gastrointestinal stromal tumors (GIST) have been reported to occasionally occur in patients with neurofibromatosis type 1 (NF1). This study aims to describe the phenotypic and genotypic characteristics of GIST in NF1 patients and attempts to elucidate the relationship between them. We analyzed GIST arising in 15 NF1 patients (8 males and 7 females, 19-82 years of age). Eleven patients had multiple GISTs (3 to >100 tumors) ranging from 1 mm to 10 cm in size and predominantly involving the small intestine including the duodenum. Tumors were symptomatic in 8 patients and incidental findings in the remaining 7 patients. Microscopically, the tumors cells were typically spindled and the mitotic rate low; 9 patients had tumors classified as very low or low risk and 6 as intermediate risk GIST. Nine patients were treated surgically and none developed metastases or died of disease. Immunohistochemical stains for CD117 were strongly positive in 47 of 50 GIST; they also accentuated hyperplastic foci (diffuse and focal) of the interstitial cells of Cajal that were often associated with microscopic GIST in the surrounding intestinal muscle wall. No KIT or PDGFRA mutations were detected in 24 GIST from 12 patients using dHPLC analysis and DNA sequencing. We conclude that patients with NF1 have a high risk of developing GIST. NF1-associated GIST are also phenotypically and genotypically distinct from sporadic GIST, indicating that different pathogenetic mechanisms are involved in their evolution.
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PMID:NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics. 1609 6

We report on the first case of benign perineurially differentiated peripheral nerve sheath tumor (perineurioma) presenting as a bleeding gastric mass in a 30-year-old, previously healthy woman with no signs or stigmata of von Recklinghausen's disease or other primary tumor at time of presentation. Gastric resection specimen revealed an ulcerated moderately cellular mesenchymal tumor consisting of elongated wavy spindle cells arranged in a fascicular and sheet-like pattern with focal whorling and occasional alternation of dark staining cellular and light staining hypocellular areas. Tumor cells were strongly immunoreactive for epithelial membrane antigen, CD56 (N-CAM), and vimentin, but were negative for S-100-protein and other lineage-specific epithelial, mesenchymal, hematolymphoid, and reticulo-histiocytic markers. CD117 revealed numerous positive staining mast cells, but the lesional cells were not reacting. We presume that the combined histological and immunohistochemical profiles of this unusual gastric neoplasm are consistent with a diagnosis of perineurioma with a probably benign biological behavior. To our knowledge, this is the first report of gastric perineurioma, an extremely rare mesenchymal lesion that should be considered among the differential diagnoses of gastrointestinal stromal tumor, especially the so-called KIT-negative GIST. Gastrointestinal perineuriomas might be under-recognized, as our case was initially diagnosed as a benign GIST.
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PMID:Perineurioma of the stomach. A rare spindle cell neoplasm that should be distinguished from gastrointestinal stromal tumor. 1613 53

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. Activating mutations of KIT or the platelet-derived growth factor receptor alpha gene (PDGFRA) have been identified in the vast majority of GISTs. The respective oncoproteins exhibit constitutive tyrosine kinase activity and promote cell growth. KIT and PDGFRA mutations are rarely found in GISTs in patients with neurofibromatosis type 1 (NF1) suggesting that the pathogenesis of GIST in NF1 patients is different from that in non-NF1 patients. Endoscopic diagnosis of GIST is usually difficult. Endoscopic ultrasonography (EUS)-guided fine-needle aspiration biopsy (EUS-FNAB) is a useful method for the diagnosis of GIST and for the detection of KIT or PDGFRA mutations. Imatinib mesylate, a tyrosine kinase inhibitor known to inhibit the activities of BCR-ABL, KIT, and PDGFR, is currently being used for the treatment of both chronic myeloid leukemia and metastatic GIST. The clinical response to imatinib therapy correlates with the types of mutations of KIT and PDGFRA, and the determination of KIT and PDGFRA mutations is useful for predicting the effect of imatinib. Resistance to imatinib after an initial response has been reported; secondary point mutations in KIT or PDGFRA that confer imatinib resistance are the most common mechanisms responsible for acquired resistance to imatinib. The continued development of target-specific therapies should increase the probability of cure in most patients with GISTs.
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PMID:Pathophysiology, diagnosis, and treatment of gastrointestinal stromal tumors. 1614 81

Interstitial cell of Cajal (ICC) hyperplasia has been documented in conditions associated with multiple gastrointestinal stromal tumours (GISTs) (familial GIST syndromes, Carney's triad and von Recklinghausen's disease) and rarely in the vicinity of sporadic GISTs. The incidence of sporadic ICC hyperplasia and the so-called seedling leiomyoma (SLM) of the lower oesophagus has not been studied in the KIT era. In a retrospective review of 77 consecutive, routinely processed oesophagogastric resection specimens for distal oesophageal carcinoma, we found foci of ICC hyperplasia in 7 of 77 (9.1%) cases and foci of SLM in 17 of 77 (22%) cases. Two types of ICC hyperplasia were recognized: a non-circumscribed type and a nodular expansile type with peripherally compressed myenteric neural tissues. All cases of ICC hyperplasia were vimentin+/CD34+/CD117+. SLMs were desmin+/vimentin(-)/CD34(-)/CD117(-), similar to smooth muscles of the gut wall. In a prospective study of 32 non-carcinomatous specimens from age-matched patients (mostly autopsy cases), we found SLMs in only one case, but we were unable to detect ICC hyperplasia in any of the cases. We concluded that sporadic KIT-positive spindle-cell hyperplasia and SLMs were unexpectedly common in distal oesophageal specimens harbouring carcinomas. The possible mechanisms leading to the development of these putative precursor lesions will be discussed.
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PMID:Sporadic Cajal cell hyperplasia is common in resection specimens for distal oesophageal carcinoma. A retrospective review of 77 consecutive surgical resection specimens. 1630 8

Functioning paraganglioma and gastrointestinal stromal tumor (GIST) are uncommon tumors that occur mostly in a sporadic and isolated form, occasionally as components of multiple neoplasia syndromes, either separately or together. Separately, they occur in several inherited syndromes including multiple endocrine neoplasia 2, and the GIST, lentigines, and mast cell tumor syndrome. Together, they are variably prominent components of three syndromes: the familial paraganglioma and gastric GIST syndrome, neurofibromatosis type 1, and the Carney triad. The two former conditions are inherited as autosomal dominant traits; the latter does not appear to be inherited and affects young women predominantly. This article reports the nonfamilial occurrence of functioning paraganglioma and GIST of the jejunum in 3 women, 1 young (22 years) at initial presentation. The occurrences were unexpected because of the infrequency of the tumors. The neoplasms, respectively, did not show germline SDHA, SDHB, SDHC, and SDHD, and KIT mutations associated with familial paraganglioma and familial GIST. The paraganglioma-jejunal GIST combination may be the harbinger of a rare genetic syndrome, a variant of the Carney triad or the paraganglioma-gastric stromal sarcoma syndrome, or be coincidental.
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PMID:Functioning paraganglioma and gastrointestinal stromal tumor of the jejunum in three women: syndrome or coincidence. 1633 Sep 41

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.
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PMID:Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. 1646 35

There is rapid evolution in the functional imaging of tumours. In two patients with concomitant pheochromocytoma and gastrointestinal stromal tumour (GIST), previously unrecognized tumours were visualized by combined 2-tracer positron emission tomography (PET), which also provided precise information about tumour type. PET imaging led to radical resection and the diagnoses were histopathologically confirmed. GISTs from the Carney patient and the patient with neurofibromatosis type 1 (NF1) both lacked KIT mutations.
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PMID:Use of 2-tracer PET to diagnose gastrointestinal stromal tumour and pheochromocytoma in patients with Carney triad and neurofibromatosis type 1. 1663 8

Previous studies have suggested that amplification of genes, notably the TOP2A gene, on chromosome arm 17q may be important for the development of malignant peripheral nerve sheath tumour (MPNST). In order to study the frequency, distribution, and chromosomal organization of rearrangements at 17q, interphase and metaphase fluorescence in situ hybridization (FISH) were used to evaluate copy number changes at 17q in 28 MPNSTs. Increased copy numbers were seen for the ERBB2 and TOP2A genes in eight and nine cases, respectively, supporting a potential role for these two genes in MPNST tumourigenesis. Net gain of distal 17q material was observed in 16 of the 28 MPNSTs, with high-level gain in three cases, and was associated with poor outcome. Among the 26 patients for whom follow-up data were available, gain of distal 17q was present in 11 of 12 tumours that had metastasized, compared with 4 of 14 of those that had not metastasized. Detailed FISH mapping analysis of metaphase spreads identified a 2 Mb commonly gained/amplified region at 17q25. Among the genes mapping to this region, BIRC5, which encodes the baculoviral IAP repeat-containing protein 5/survivin protein, is a strong candidate target gene for amplification, as it has been previously shown to be overexpressed in neurofibromatosis type 1-associated MPNST. Three other genes that co-amplified with BIRC5 represent other potential candidate genes: PTDSR involved in apoptosis; SEPT9 overexpressed in human malignant brain tumours; and SOCS3 involved in cell survival and differentiation of neurons.
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PMID:Identification of a novel amplicon at distal 17q containing the BIRC5/SURVIVIN gene in malignant peripheral nerve sheath tumours. 1672 26

The association between Achondroplasia and Neurofibromatosis type 1 has been described in only three patients. We report the clinical features and molecular characterization of a new patient with de novo ACH and NF1, providing for the first time a detailed clinical and molecular evaluation. Even if this association seems coincidental, some startling, intriguing correlations are discussed at the clinical and molecular level, between ACH, NF, and the existence of a common "mutator" genotype.
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PMID:The strange association between achondroplasia and neurofibromatosis type 1: molecular analysis of a new patient and review of the literature. 1697 43

Neuroendocrine tumors are very heterogeneous, develop from a variety of tissues, and can be difficult to diagnose. Without the clinical manifestation of metastases, it is often difficult to characterize them as malignant. Even so-called completely (R0) resected tumors can spread clinically visible metastases within a few months after initial surgery. Treatment options for neuroendocrine tumors including pheochromocytoma are limited. Molecular targeted therapies using tyrosine kinase inhibitors might prove to be helpful in patients with these tumors. In an immunohistochemical study, we examined KIT in 26 pheochromocytomas, 8 of which were malignant (3 adrenal pheochromocytomas, 5 paragangliomas). KIT expression was found in one of these 8 malignant tumors. This 2.5-cm-large adrenal pheochromocytoma originated from a woman with neurofibromatosis type 1 and spread into spine, skull, and lung. KIT expression could be demonstrated in 5% of tumor cells. On the basis of KIT expression immunohistochemically, we treated patients with neuroendocrine (i.e., medullary thyroid cancer) and other tumors with imatinib 400 mg per day, but without efficacy after 2 months of therapy. Similar results were shown by other investigators. Therefore, monotherapy with imatinib may not be efficacious in patients with neuroendocrine tumors that express KIT. Tyrosine kinase inhibitors such as sorafenib that targets several receptors in addition to KIT may be more efficacious in treating patients with neuroendocrine tumors.
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PMID:Does the expression of c-kit (CD117) in neuroendocrine tumors represent a target for therapy? 1710 20


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