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)

Previous studies have shown that Imatinib mesylate (Gleevec), a selective tyrosine kinase inhibitor of c-KIT and platelet-derived growth factor receptors (PDGFR), is highly effective in c-KIT/CD117-positive gastrointestinal stromal tumors (GIST), especially in those having activating mutations in c-kit exon 11. In addition, gain-of-function mutations in the juxtamembrane domain (exon 12) and the kinase activation loop (exon 18) of PDGFRalpha were found in GISTs. Importantly, the presence and type of these mutually exclusive c-KIT or PDGFRalpha mutations were found to be associated with the response to imatinib. Here, we examined the prevalence of c-kit exon 11 and PDGFRalpha exons 12 and 18 mutations in other tumor types known to express these tyrosine kinase receptors in order to explore which other cancer types may potentially benefit from imatinib treatment. We determined the mutational status of these commonly mutated exons by direct sequencing in 11 different tumor types (in total: 215 unrelated cases), including GIST, chordoma, and various distinct tumors of lung, brain and its coverings, and skin cancer. Of the 579 exons examined (211 c-kit exon 11, 192 PDGFRalpha exon 12, 142 PDGFRalpha exon18, 17 PDGFRbeta exon 12 and 17 PDGFRbeta exon 18), only 12 (all GIST) harbored mutations (10 c-kit exon 11 and 2 PDGFRalpha exon18). From these data we conclude that activating c-KIT and PDGFR mutations are sporadic in human cancers known to overexpress these tyrosine kinase receptor genes and suggest that, except in GIST, this overexpression is not correlated with activating mutations. The latter may imply that these wild-type c-KIT and PDGFR tumor types will probably not benefit from imatinib treatment.
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PMID:Activating mutations in c-KIT and PDGFRalpha are exclusively found in gastrointestinal stromal tumors and not in other tumors overexpressing these imatinib mesylate target genes. 1632 88

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

Although activator protein 2gamma (AP-2gamma) has been reported to be a marker of germ cell tumors of the testis, its relationship to placental alkaline phosphatase (PLAP) and KIT (CD117) protein expression in intratubular germ cell neoplasia (ITGCN) has not been directly compared. In this study, staining of AP-2gamma in 30 cases of ITGCN was examined and compared with that of PLAP and KIT. Both PLAP and KIT were positive in 29 (97%) of 30 cases, whereas AP-2gamma was expressed in 100%. All 3 markers were negative in normal testis (0 of 11 cases). DNA binding sites in the promoter region forAP-2gamma in the PLAP and c-kit genes might explain the concordance of protein expression.
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PMID:AP-2gamma protein expression in intratubular germ cell neoplasia of testis. 1641 36

The proto-oncogene c-KIT (CD117) is highly expressed in normal breast epithelium and is decreased in invasive breast cancer. In this study, we analyzed the protein expression and the mutational status of c-KIT in ductal carcinoma in situ (DCIS) of the breast and correlated these findings with nuclear grade, architectural pattern, and expression of HER-2, estrogen receptor (ER)-alpha, and progesterone receptor (PR). C-KIT, HER-2, ER, and PR expression were analyzed immunohistochemically in 106 cases of paraffin-embedded DCIS (85 pure DCIS and 21 DCIS with concurrent carcinoma). Direct sequencing of exons 9 and 11 of the c-KIT gene was performed to analyze the hot spot mutational regions in representative cases. C-KIT expression was found in 55 (52.8%) of all DCIS, correlating with high nuclear grade (P < .0001), comedonecrosis (P < .0001), and solid growth pattern (P = .001). Furthermore, c-KIT expression was strongly associated with HER-2 positivity (P < .0001) and was significantly lower in ER- or PR-positive cases (P = .001 and P = .006, respectively). C-KIT expression alone or co-expression with HER-2 in pure DCIS did not differ significantly from DCIS with invasive component (P = .09). Mutational analysis in 6 c-KIT-positive DCIS revealed no activating mutations in exons 9 or 11. Our findings suggest that the expression of c-KIT protein might define a subset of poorly differentiated, HER-2-positive DCIS with decreased expression of steroid hormone receptors, comedonecrosis, and a solid growth pattern. The implications of c-KIT and HER-2 co-expression for breast carcinogenesis should be further evaluated.
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PMID:C-KIT expression in ductal carcinoma in situ of the breast: co-expression with HER-2/neu. 1642 21

Metastatic gastrointestinal stromal tumors (GIST) have an extremely poor prognosis; however, their immunohistochemical and genetic features have not been assessed satisfactorily and the mechanisms responsible for their high malignant potential remain unclear. We examined the immunohistochemical differences between gastric GIST and metastatic lesions in the liver of four patients who had undergone a postgastrectomy hepatectomy for metachronous liver metastases. We also carried out genetic analysis of the tumors in three of the four cases. In all cases, the immunoreactivity profiles, including KIT (CD117), CD34, smooth muscle actin (SMA), desmin, S-100 and vimentin, were similar between the gastric and metastatic tumors, but the Ki67 labeling index in the metastatic GIST was higher than that of the primary GIST. Interestingly, in the case who had received neoadjuvant imatinib therapy before gastrectomy, its therapeutic effect was observed in most of the primary lesion, with the exception of a specific small area with high cellularity. Genetic analysis revealed no acquired mutations in the c-kit or PDGFRA genes in the metastatic lesions in any of the patients, but loss of heterozygosity (LOH) of the c-kit gene was observed mainly in the metastatic tumors in two of the three cases. Furthermore, in the case of neoadjuvant imatinib therapy, LOH of the c-kit gene was shown in the high cellularity area in the primary lesion and metastatic liver GIST. It is suggested that LOH of the c-kit gene is an important event that leads to imatinib resistance and metastatic progression of GIST. In conclusion, both gastric and metastatic GIST had almost the same immunohistochemical features, except for their proliferative activity, and LOH of the c-kit gene played an important role in the process of liver metastasis.
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PMID:Immunohistochemical and genetic features of gastric and metastatic liver gastrointestinal stromal tumors: sequential analyses. 1644 23

Gastrointestinal stromal tumors (GISTs), the most common nonepithelial neoplasms of the gastrointestinal (GI) tract, occur most commonly in the stomach. These neoplasms were previously classified as smooth muscle tumors, but it has become apparent that they represent distinct clinicopathologic entities. All GISTs should be considered as having malignant potential, although they display varying degrees of aggressiveness. Although usually asymptomatic, large GISTs may present with pain or bleeding. Definitive diagnosis is made by immunohistochemical staining of the tissue for CD117, also known as KIT protein, a cell membrane receptor with tyrosine kinase activity. Size and mitotic activity are predictive of malignant behavior. Primary treatment for GISTs with high malignant potential is surgical resection. Specific therapy targeting the KIT receptor with imatinib has resulted in improved outcomes for patients with unresectable, metastatic, and recurrent disease.
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PMID:Gastrointestinal stromal tumor (GIST). 1653 79

The authors studied the concordance among seven pathologists for the histologic diagnosis, interpretation of KIT immunostaining, and determining MIB-1 labeling indices (LI) in 80 adult patients with primary spindle cell tumors, mainly of the gastrointestinal tract, mesentery, retroperitoneum, and pelvis, based on the review of tissue sections using an immunohistochemical panel of antibodies for KIT/CD117, CD34, desmin, smooth muscle actin (SMA), and S-100 protein. Tumors included 30 gastrointestinal stromal tumors (GISTs), 10 leiomyomas, 10 leiomyosarcomas, 10 schwannomas, 10 solitary fibrous tumors, and 10 desmoid-type fibromatoses. The overall concordance with the original diagnosis of each histologic type was 97.9%, the kappa value ranging from 0.95 to 1.00 (mean 0.97), indicating a perfect agreement. The overall interlaboratory concordance with the original interpretation of KIT immunostaining was 91.3%, the kappa value ranging from 0.77 to 0.90 (mean 0.86). The overall interlaboratory concordance with the original interpretation of KIT immunostaining was 91.9%, the kappa value ranging from 0.72 to 0.93 (mean 0.85). The overall concordance for determining MIB-1 LI was 90% with the original evaluation, and the overall kappa value ranged from 0.62 to 0.86 (mean 0.77). These results indicate that it is possible to reliably diagnose GIST and other spindle cell tumors of the gastrointestinal tract with the use of an immunohistochemical panel of antibodies for KIT, CD34, desmin, SMA, and S-100 protein. Although there is clearly unavoidable inter-observer and interlaboratory variability in the interpretation of KIT immunostained sections and interobserver variability in the determination of MIB-1 LI, the concordance between observes is very acceptable, and in most instances such variability can be eliminated by careful reviewing of the hematoxylin and eosin and immunostained sections.
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PMID:Interobserver variability in histologic recognition, interpretation of KIT immunostaining, and determining MIB-1 labeling indices in gastrointestinal stromal tumors and other spindle cell tumors of the gastrointestinal tract. 1654 Jul 30

Gastrointestinal stromal tumours (GISTs) are most common in the stomach (60-70%), followed by small intestine (20-25%), colon and rectum (5%), and esophagus (<5%). They are characterized by expression of the transmembrane receptor tyrosine kinase KIT, which is defined by the CD117 antigen and is the product of the kit proto-oncogene. Metastatic risk is based on tumour size and mitotic count. The treatment options have evolved rapidly with the discovery of imatinib (Gleevec) that selectively inhibits KIT. Complete resection without tumour rupture remains the mainstay of treatment in patients with localized, resectable disease. Imatinib has been shown to be the first successful systemic therapy for patients with metastatic or unresectable disease and is also currently being tested as an adjuvant therapy after the resection of high risk primary GIST. New blockers of the tyrosine-kinase activity are currently in development in cases of resistance.
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PMID:[Diagnosis and treatment of gastrointestinal stromal tumours]. 1662 79

We have recently described a CD19(-) B220(+)CD117(low) bone marrow subpopulation with B, T, and myeloid developmental potential, which we have called "early progenitors with lymphoid and myeloid potential" or EPLM. These cells also expressed Fms-like tyrosine kinase 3, Flt3, or CD135. Treatment of mice with the corresponding ligand, Flt3L, showed a 50-fold increase in EPLM. In addition to the expected increase in dendritic cell numbers, Flt3L treatment had a reversible inhibitory effect on B lymphopoiesis. Limiting dilution analysis of sorted EPLM from Flt3L-treated mice showed that B-lymphocyte progenitor activity was reduced 20-fold, but that myeloid and T-cell progenitor activity was largely preserved. EPLM from treated mice transiently reconstituted the thymus and bone marrow of recipient mice, generating cohorts of functional T and B cells in peripheral lymphoid organs. Thus, Flt3L treatment results in a dramatic increase in a novel bone marrow cell with lymphoid and myeloid progenitor activity.
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PMID:Increasing Flt3L availability alters composition of a novel bone marrow lymphoid progenitor compartment. 1667 11

Accurate preoperative diagnosis for gastrointestinal stromal tumor (GIST) was obtained using the endoscopic approach in about 50% of the cases. Preoperative assessment is quite important in reproductive women for the treatment of pelvic tumor. We report the first case of GIST of the rectum that was accurately diagnosed with preoperative needle biopsy from the vaginal wall. The case was a 38-year-old woman who presented with a history of genital bleeding. Internal examination revealed a round and elastic mass (7 x 7 cm) in the left pelvic cavity. The biopsy specimen from the left sidewall of the vagina using a manually manipulated biopsy needle showed strong reaction for CD34 and CD117 (c-KIT). The patient underwent low anterior resection of the rectum, tumor resection, and partial resection of the posterior vagina. Preoperative biopsy with vaginal approach might be helpful to make a diagnosis for pelvic tumor of unknown origin and unknown malignant potential.
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PMID:Preoperative needle biopsy and immunohistochemical analysis for gastrointestinal stromal tumor of the rectum mimicking vaginal leiomyoma. 1668 89


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