Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fourteen primary human lung tumor DNAs from smokers were analyzed for transforming activity by two DNA transfection assays. Activated protooncogenes were detected in 3 of 11 tumor DNAs by the NIH 3T3 focus assay, whereas activated protooncogenes were detected in 11 of 13 tumor DNAs by the NIH 3T3 cotransfection-nude mouse tumorigenicity assay. K- or NRAS genes activated by point mutation at codons 12 or 61 were detected in a large cell carcinoma, a squamous cell carcinoma, and 5 adenocarcinomas. An HRAS oncogene activated by a different mechanism was detected in an epidermoid carcinoma. One adenocarcinoma was found to contain an activated RAF gene. Two unidentified transforming genes were detected in a squamous cell carcinoma DNA and two adenocarcinoma DNAs. Eight of 10 lung adenocarcinomas that had formed metastases at the time of surgery were found to contain RAS oncogenes. No significant increase in metastasis was observed in the lung adenocarcinomas that contained one or more 6-kilobase EcoRI alleles of the LMYC gene. Overall, 12 of 14 (86%) of the lung tumor DNAs from smokers were found to contain activated protooncogenes. RAS oncogenes appear to play a role in the development of metastases in lung adenocarcinomas.
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PMID:Activated protooncogenes in human lung tumors from smokers. 199 9

To evaluate the timing of mutations in BRAF (v-raf murine sarcoma viral oncogene homolog B1) during melanocytic neoplasia, we carried out mutation analysis on microdissected melanoma and nevi samples. We observed mutations resulting in the V599E amino-acid substitution in 41 of 60 (68%) melanoma metastases, 4 of 5 (80%) primary melanomas and, unexpectedly, in 63 of 77 (82%) nevi. These data suggest that mutational activation of the RAS/RAF/MAPK pathway in nevi is a critical step in the initiation of melanocytic neoplasia but alone is insufficient for melanoma tumorigenesis.
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PMID:High frequency of BRAF mutations in nevi. 1244 72

We examined mutations in BRAF exons 11 and 15 and N-RAS exons 2 and 3, in 77 metastatic melanoma cases and 11 melanoma cell lines. Significant differences in the mutation rates observed at different metastatic sites could not be detected. The most frequent mutation, the V599E amino acid substitution in BRAF exon 15, was observed in 31 of 77 (40%) tissues and 5 of 11 (45%) cell lines. Tandem base-pair substitutions encoding V599R and V599K amino acid changes were observed in two cases. Novel findings with respect to melanoma include a cell line possessing a 2 base-pair substitution in BRAF exon 11 and a case harboring mutations in both BRAF exon 11 and N-RAS exon 3. Our data show that BRAF mutation is common in melanoma metastases, regardless of their site, that mutations include both exons 11 and 15, and suggest that anti-RAS/RAF strategies may be effective in metastatic melanoma patients.
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PMID:Analysis of BRAF and N-RAS mutations in metastatic melanoma tissues. 1287 90

RAF proteins are serine/threonine kinases that mediate cellular responses to growth signals by activating the mitogen-activated protein kinase pathway. Mutations in the BRAF gene causing a V599E amino acid substitution that enhance the kinase activity have been described in >60% of cutaneous melanomas and premalignant melanocytic lesions. We have investigated the frequency of BRAF mutations at the expression level in melanomas of the uveal tract. None of the 30 metastases and 10 primary uveal melanomas tested expressed the V599E mutation. In contrast, this mutation was expressed by 65% of cutaneous melanoma samples, confirming previous results. In addition, a double mutation resulting in V599K substitution was detected in two suspect ocular metastases of cutaneous melanoma. Analysis of exon 11, the second common site of BRAF mutations, revealed only wild-type sequences in uveal melanomas. Analysis of tumor lysates showed the presence of phosphorylated mitogen-activated protein kinase, kinase, and mitogen-activated protein kinase in 50% of uveal and 100% of cutaneous melanoma metastases. Taken together, these results suggest that although the common BRAF mutations found in cutaneous melanoma do not play a role in tumorigenesis of uveal tract melanocytes, activation of the RAF/mitogen-activated protein kinase pathway may nevertheless play an important role in uveal melanoma.
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PMID:Lack of BRAF mutations in uveal melanoma. 1452 89

The RAS/RAF/MAPK pathway likely mediates critical cell proliferation and survival signals in melanoma. BRAF mutations have been found in a high percentage of melanoma cell lines and metastases; however, only a few studies with a limited number of specimens have focused on primary melanomas. We examined BRAF exon 15 mutational status in 37 primary invasive melanomas of varying thicknesses, which had undergone a standardized pathology review. BRAF mutational status was determined using direct manual sequencing of PCR products, followed by resequencing separately amplified DNA aliquots to confirm each mutation. BRAF exon 15 mutations were found in 17 of 37 (46%) primary melanomas. Tumor-specific tandem mutations, encoding either V599K, V599R, or V599E, were found in 5 of 17 (29%) melanomas with BRAF exon 15 mutations. Cloning of BRAF double base-pair substitutions confirmed that both base changes were on the same allele and can result in a positive charge at codon 599. BRAF mutations, including tandem mutations, were frequently found in both thin and thick primary melanomas, implying that these mutations can occur early in the progression of melanoma. The finding of tandem mutations in thin melanomas makes it more likely that they arise as a simultaneous rather than sequential event.
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PMID:Tandem BRAF mutations in primary invasive melanomas. 1514 Feb 48

The number of effective cytotoxic agents for the treatment of patients with metastatic adult soft tissue sarcoma is limited, especially when patients have failed anthracycline- and ifosfamide-based chemotherapy. For the subgroup of patients with inoperable gastrointestinal stromal tumour (GIST), progress has been made via the rapid development and approval of the targeted therapy imatinib. Small round cell tumours (SRCTs), such as Ewing's sarcoma/primitive neuroectodermal tumour, desmoplastic SRCT and rhabdomyosarcoma, are chemotherapy-sensitive and potentially curable malignancies, which are treated with multimodality, dose-intensive, neoadjuvant protocols regardless of size or overt metastatic disease. Most other high-grade (grading >I), so-called 'adult type', soft tissue sarcomas such as fibrosarcoma, liposarcoma, pleomorphic and synovial sarcomas are treated with an anthracycline-based regimen with or without ifosfamide as front-line therapy. In relapsed 'adult type' soft tissue sarcomas, trofosfamide, gemcitabine and trabectedin (ecteinascidin 743) appear to be drugs associated with some activity and an acceptable toxicity profile. A high activity has been reported for the taxanes, in particular for paclitaxel, in vascular sarcomas located in the scalp or face and in Kaposi's sarcoma. It is interesting to note that the different drugs have particular effects in distinct subtypes of soft tissue sarcoma; however, it should be taken into account that the number of patients included in the phase II trials is limited. The role of the newer agents (e.g. epothilones, brostallicin) is currently undefinable. Targeted therapy inhibiting vascular endothelial growth factor receptor, epidermal growth factor receptor, RAF kinase, c-KIT or platelet-derived growth factor receptors will continue to be tested in GIST patients refractory to imatinib and in other sarcoma histologies.
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PMID:Recent developments in salvage chemotherapy for patients with metastatic soft tissue sarcoma. 1563 40

Melanoma is a form of skin cancer that has a poor prognosis and which is on the rise in Western populations. If detected early, it is easily treated by surgical excision. However, once melanoma metastasises it is notoriously resistant to existing therapies and for many patients the outlook is dismal. Thus a full description of melanoma etiology and a full understanding of the genetic lesions that underlie this disease is required to allow us to develop new and effective therapeutic strategies for its treatment. RAF proteins are a family of serine/threonine-specific protein kinases that form part of a signalling module that regulates cell proliferation, differentiation and survival. In mammals there are three isoforms, A-RAF, B-RAF and C-RAF, and recently it was shown that the B-RAF isoform is mutated in a high proportion of melanomas. In light of these exciting findings, we review what we have learned about B-RAF and its role in cutaneous melanoma.
Cancer Metastasis Rev 2005 Jan
PMID:The role of B-RAF in melanoma. 1578 79

Angiogenesis is a hallmark of melanoma progression. Antiangiogenic agents have been infrequently tested in patients with advanced melanoma. Experience with most other cancers suggests that single-agent application of angiogenic inhibitors is unlikely to have substantial clinical antitumor activity in melanoma. It is more likely that combinations of antiangiogenic agents with either chemotherapy or other targeted therapy will be needed to produce significant clinical benefit. In melanoma, numerous cellular pathways important to cell proliferation, apoptosis, or metastases have recently been shown to be activated. Activation occurs through specific mutations (B-RAF, N-RAS, and PTEN) or changes in expression levels of various proteins (PTEN, BCL-2, NF-kappaB, CDK2, and cyclin D1). Agents that block these pathways are rapidly entering the clinical setting, including RAF inhibitors (sorafenib), mitogen-activated protein kinase inhibitors (PD0325901), mammalian target of rapamycin inhibitors (CCI-779), and farnesyl transferase inhibitors (R115777) that inhibit N-RAS and proteasome inhibitors (PS-341) that block activation of nuclear factor-kappaB (NF-kappaB). It will be a challenge to evaluate these agents alone, in combination with each other, or with chemotherapy in patients with melanoma. Trials with large populations of biologically ill-defined tumors run the risk of missing clinical antitumor activity that is important for a particular yet-to-be-defined subset of patients. To rationally and optimally develop these targeted agents, it will be critical to adequately test for the presence of the presumed cellular target in tumor specimens and the effect of therapy on the proposed target (biological response). Investigators in this field will need to carefully plan these trials so that at the end of the day, we learn from both the failures and successes of targeted therapy.
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PMID:Molecular targets in melanoma from angiogenesis to apoptosis. 1660 62

Malignant melanoma originates in melanocytes, the pigment-producing cells of the skin and eye, and is one of the most deadly human cancers with no effective cure for metastatic disease. Like many other cancers, melanoma has both environmental and genetic components. For more than 20 years, the melanoma genome has been subject to extensive scrutiny, which has led to the identification of several genes that contribute to melanoma genesis and progression. Three molecular pathways have been found to be nearly invariably dysregulated in melanocytic tumors, including the RAS-RAF-MEK-ERK pathway (through mutation of BRAF, NRAS or KIT), the p16 INK4A-CDK4-RB pathway (through mutation of INK4A or CDK4) and the ARF-p53 pathway (through mutation of ARF or TP53). Less frequently targeted pathways include the PI3K-AKT pathway (through mutation of NRAS, PTEN or PIK3CA) and the canonical Wnt signaling pathway (through mutation of CTNNB1 or APC). Beyond the specific and well-characterized genetic events leading to activation of proto-oncogenes or inactivation of tumor suppressor genes in these pathways, systematic high-resolution genomic analysis of melanoma specimens has revealed recurrent DNA copy number aberrations as well as perturbations of DNA methylation patterns. Melanoma provides one of the best examples of how genomic analysis can lead to a better understanding of tumor biology. We review current knowledge of the genes involved in the development of melanoma and the molecular pathways in which these genes operate.
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PMID:The genome and epigenome of malignant melanoma. 1804 49

Gastrointestinal stromal tumors (GISTs) generally arise from primary activating mutations in the KIT or PDGFRA genes that result in constitutive activation of receptor tyrosine kinase activity. Imatinib provides targeted therapy for GIST by inhibiting the KIT and PDGFR-alpha tyrosine kinases. Clinical benefit is achieved in approximately 85% of patients with unresectable or metastatic disease, with a median progression-free survival of 20 to 24 months. The mechanisms of acquired resistance to imatinib are heterogeneous, with most involving the emergence of secondary mutations in KIT exons 13, 14, or 17. In patients failing or intolerant to imatinib, the multitargeted agent sunitinib achieves durable disease control in approximately 50% of cases. Experimental treatment options beyond those currently available consist of other KIT-targeting tyrosine kinase inhibitors, such as nilotinib, or agents targeting alternative pathways, such as antiangiogenic agents, mammalian target of rapamycin, RAF kinase, and chaperone inhibitors.
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PMID:Novel approaches to imatinib- and sunitinib-resistant GIST. 1877 61


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