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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The process of proliferation, invasion and metastasis is a complex one which involves both the autonomy of the malignant cells and their interaction with the cellular and extracellular environments. The way in which the tumor cells respond to cellular and extracellular stimuli is regulated through transduction of those signals and translation into cellular activity. Transmembrane signal transduction involves three major categories of events: ion channel activation, transmission through guanine nucleotide binding protein intermediates with production of second messengers, and phosphorylation events. A frequent common denominator of these different pathways is a cellular calcium homeostasis. Calcium may be both a result of and a regulator of many of these signal transduction pathways and has been shown to have a role in the regulation of proliferation, invasion, and metastatic potential. The understanding and application of the basic tenets of these pathways to tumor cell proliferation, invasion, and metastases opens a new target for therapeutic intervention. We have identified a novel agent, CAI, which through inhibition of stimulated calcium influx inhibits proliferation and migration in vitro, and growth and dissemination in human cancer xenografts in vivo. CAI offers a new approach to cancer therapy, signal transduction therapy.
Cancer Metastasis Rev 1994 Mar
PMID:Calcium-mediated signal transduction: biology, biochemistry, and therapy. 814 44

The most frequently detected oncogene alterations, both in animal and human cancers, are the mutations in the ras oncogene family. These oncogenes are mutated or overexpressed in many human tumors, with a high incidence in tumors of the pancreas, thyroid, colon, lung and certain types of leukemia. Ras is a small guanine nucleotide binding protein that transduces biological information from the cell surface to cytoplasmic components within cells. The signal is transduced to the cell nucleus through second messengers, and it ultimately induces cell division. Oncogenic forms of p21(ras) lead to unregulated, sustained signaling through downstream effectors. The ras family of oncogenes is involved in the development of both primary tumors and metastases making it a good therapeutic target. Several therapeutic approaches to cancer have been developed pointing to reducing the altered gene product or to eliminating its biological function: (1) gene therapy with ribozymes, which are able to break down specific RNA sequences, or with antisense oligonucleotides, (2) immunotherapy through passive or active immunization protocols, and (3) inhibition of p21(ras) farnesylation either by inhibition of farnesyl transferase or synthesis inhibition of farnesyl moieties.
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PMID:Inhibition of ras oncogene: a novel approach to antineoplastic therapy. 1089 51

Uveal melanoma represents the most common primary intraocular malignancy in adults. Although uveal and cutaneous melanomas both arise from melanocytes, uveal melanoma is clinically and biologically distinct from its more common cutaneous counterpart. Metastasis occurs frequently in this disease, and once distant spread occurs, outcomes are poor. No effective systemic therapies are currently available; however, recent advances in our understanding of the biology of this rare and devastating disease, combined with the growing availability of targeted agents, which can be used to rationally exploit these findings, hold the promise for novel and effective therapies in the foreseeable future. Herein, we review our rapidly growing understanding of the molecular biology of uveal melanoma, including the pathogenic roles of GNAQ (guanine nucleotide binding protein q polypeptide)/11, PTEN (phosphatase and tensin homolog), IGF (insulin-like growth factor)/IGF-1 receptor, MET (hepatocyte growth factor), BAP1 [breast cancer 1, early onset (BRCA1)-associated protein-1], and other key molecules, potential therapeutic strategies derived from this emerging biology, and the next generation of recently initiated clinical trials for the treatment of advanced uveal melanoma.
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PMID:Therapeutic implications of the emerging molecular biology of uveal melanoma. 2144 80

The aim of the study was to investigate the molecular genetics of uveal melanoma (UM) metastases and correlate it with disease progression. Twelve pathologically confirmed UM metastases from 11 patients were included. Molecular genetic alterations in chromosomes 3 (including the BAP1 region), 8q, 6p, and 1p were investigated by microsatellite genotyping. Mutations in codon 209 of GNAQ and GNA11 genes were studied by restriction-fragment length polymorphism (RFLP). We identified monosomy of chromosome 3 in tumors from four patients with an average survival of 5 months (range 1-8 months) from time of diagnosis of metastatic disease. In contrast, tumors with either disomy or partial chromosome 3 alterations showed significantly slower metastatic disease progression with an average survival of 69 months (range 40-123 months, p = 0.003). Alterations in chromosomal arms 1p, 6p, and 8q and mutations in either GNAQ or GNA11 showed no association with disease progression. Prominent mononuclear inflammatory infiltrate was observed in tumors from patients with slowly progressive disease. In conclusion, in UM metastases, monosomy 3 is associated with highly aggressive, rapidly progressive disease while disomy or partial change of 3 and prominent mononuclear inflammatory infiltrate in the tumor is associated with better prognosis. These findings should be considered when designing clinical trials testing effectiveness of various therapies of metastatic UM.
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PMID:Monosomy 3 status of uveal melanoma metastases is associated with rapidly progressive tumors and short survival. 2256 40

Blue nevi are a clinically and pathologically heterogeneous group of benign pigmented dermal melanocytic tumors that may exhibit histologic overlap with malignant melanoma. This study evaluates the role of immunohistochemical and molecular analyses in the classification and differential diagnosis between blue nevi and melanoma. Twenty-three dermal melanocytic tumors, initially diagnosed as benign or ambiguous, were subjected to immunohistochemical staining for phosphohistone H3 and MIB-1 to evaluate mitotic activity, comparative genomic hybridization to detect chromosomal aberrations, and GNAQ, GNA11, BRAF, NRAS, and KRAS sequencing. Of 19 patients with follow-up information (median, 1.6 years), 3 developed recurrent or metastatic disease. Nevertheless, 11 of the 19 patients with follow-up had <2 years of follow-up. Nine of 23 patients showed chromosomal aberrations, including all 3 patients with tumor recurrence or progression. There was no significant correlation between mutation status (P = 0.6) or mitotic rate (P = 0.3) and outcome. In conclusion, three of nine patients with chromosomal aberrations developed tumor recurrence or progression. Patients with histologically ambiguous dermal melanocytic proliferations that exhibit copy number aberrations should undergo careful clinical follow-up.
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PMID:Proliferative activity, chromosomal aberrations, and tumor-specific mutations in the differential diagnosis between blue nevi and melanoma. 2326 Dec 61

Uveal melanoma (UM) is the second-most common form of melanoma and the most common primary intraocular malignancy. Up to one-half of patients are at risk for fatal metastatic disease. The metastatic potential of an individual tumor can be accurately determined by analysis of a fine-needle aspirate with gene expression profiling assay that is available for routine clinical use through a commercial Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. The test renders one of two results-class 1 (low metastatic risk) or class 2 (high metastatic risk)-and has been extensively validated in multiple centers. Until recently, the genetic mutations and signaling aberrations in UM were largely unknown. With the advent of new genomic sequencing technologies, however, the molecular landscape of UM is rapidly emerging. Mutations in the Gq alpha subunits GNAQ and GNA11 are mutually exclusive and represent early or initiating events that constitutively activate the MAPK pathway. Mutations in BRCA1-associated protein-1 (BAP1) and splicing factor 3B subunit 1 (SF3B1) also appear to be largely mutually exclusive, and they occur later in tumor progression. BAP1 mutations are strongly associated with metastasis, whereas SF3B1 mutations are associated with a more favorable outcome. BAP1 mutations can arise in the germ line, leading to a newly described BAP1 familial cancer syndrome. These discoveries have led to new clinical trials to assess several classes of compounds, including MEK, protein kinase C, and histone deacetylase inhibitors, in the adjuvant setting for high-risk patients identified as class 2, as well as in the setting of advanced disseminated disease.
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PMID:Genomic, prognostic, and cell-signaling advances in uveal melanoma. 2371 57

Uveal melanoma is the most common primary intraocular tumour in Caucasians. There are approximately 500 new cases of uveal melanoma in Germany per year and the incidence rate peaks at the age of 70 years. Half of all uveal melanoma patients develop metastatic disease, which can be observed even many years after successful treatment of the primary tumour. In most cases the liver is the location of first manifestation. Based on the chromosome 3 status uveal melanomas can be divided into two major classes that differ in their metastatic potential. Tumours with a high risk to metastasise usually show monosomy 3, whereas tumours showing disomy 3 rarely metastasise. If a patient wishes to know about his individual risk, prognostic testing of the primary tumour tissue can be performed after obtaining tumour material via transscleral or transretinal biopsy, or by enucleation. To date results of prognostic testing do not influence therapeutic strategies. Recently, major key genes involved in uveal melanoma development, GNAQ, GNA11, BAP1, SF3B1 and EIF1AX, have been identified. Mutation profiling, in addition to chromosomal 3 analysis, will further refine the classification or subclassification of uveal melanomas and will hopefully influence diagnostic or therapeutic concepts. Hereditary mutations in tumour suppressor gene BAP1 are associated with an increased risk for different tumour entities. Detection of germ line mutations in this tumour suppressor gene should implicate further general screening examinations of the patient to be able to detect these tumour entities. Moreover relatives of these patients should be offered a screening for BAP1 mutation.
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PMID:[Uveal melanoma: current insights into clinical relevance of genetic testing]. 2387 23

Uveal melanoma is the most common malignant tumor of the adult eye. Fifty percent of tumors will eventually metastasize, and there are no effective treatments for them. Recent studies of uveal melanoma have identified activating mutations in GNAQ and GNA11, loss-of-function mutations in the tumor suppressor gene BAP1, and recurrent mutations in codon 625 of SF3B1. Previous studies have reported the existence of a higher frequency of GNA11 than GNAQ mutations, frequent BAP1 loss, and rare SF3B1 mutations in metastatic uveal melanoma. We analyzed a cohort of 30 uveal melanoma metastases for the occurrence of GNAQ, GNA11, and SF3B1 mutations, as well as BAP1 loss, and correlated these parameters with clinical and histopathologic features. Most (92%) tumors were composed of cells with an epithelioid or mixed (<100% spindle cells) morphology. Tumor samples composed exclusively of spindle cells were rare (n=2, 8%). Most tumors showed a moderate to marked degree of nuclear pleomorphism (n=24, 96%), and contained hyperchromatic, vesicular nuclei with variably conspicuous nucleoli. GNA11 mutations were considerably more frequent than GNAQ mutations (GNA11, GNAQ, and wild-type in 18 (60%), 6 (20%), and 6 (20%) cases, respectively). SF3B1 mutation was found in 1 of 26 tumors (4%), whereas loss of BAP1 expression was present in 13 of 16 tumors (81%). Patients with GNA11-mutant tumors had poorer disease-specific survival (60.0 vs 121.4 months, P=0.03) and overall survival (50.6 vs 121.4 months, P=0.03) than those with tumors lacking GNA11 mutations. The survival data, combined with the predominance of GNA11 mutations in metastases, raises the possibility that GNA11-mutant tumors may be associated with a higher risk of metastasis and poorer prognosis than GNAQ-mutant tumors. Further studies of uveal melanoma are required to investigate the functional and prognostic relevance of oncogenic mutations in GNA11 and GNAQ.
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PMID:Genetic and clinico-pathologic analysis of metastatic uveal melanoma. 2388 4

Melanoma of unknown primary (MUP) is an uncommon phenomenon whereby patients present with metastatic disease without an evident primary site. To determine their likely site of origin, we combined exome sequencing from 33 MUPs to assess the total rate of somatic mutations and degree of UV mutagenesis. An independent cohort of 91 archival MUPs was also screened for 46 hot spot mutations highly prevalent in melanoma including BRAF, NRAS, KIT, GNAQ, and GNA11. Results showed that the majority of MUPs exhibited high somatic mutation rates, high ratios of C>T/G>A transitions, and a high rate of BRAF (45 of 101, 45%) and NRAS (32 of 101, 32%) mutations, collectively indicating a mutation profile consistent with cutaneous sun-exposed melanomas. These data suggest that a significant proportion of MUPs arise from regressed or unrecognized primary cutaneous melanomas or arise de novo in lymph nodes from nevus cells that have migrated from the skin.
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PMID:Melanomas of unknown primary have a mutation profile consistent with cutaneous sun-exposed melanoma. 2389 Jan 54

Primary melanocytic neoplasms of the central nervous system (CNS) are uncommon and must be distinguished from metastatic lesions as patients with metastatic disease carry a worse prognosis. Therefore, tools to aid in the diagnosis of a primary CNS melanocytic neoplasm would be of clinical utility. Primary CNS melanocytic neoplasms, including uveal melanomas have frequent mutations in GNAQ and GNA11, but are rare in cutaneous and mucosal melanomas. Additionally, primary uveal melanomas often exhibit monosomy 3 conferring an elevated risk of metastasis. We present a 63 year-old male with a melanocytic neoplasm in the thoracic spinal cord. Molecular studies revealed the tumor contained a GNAQ mutation and four-color fluorescent in situ hybridization (FISH) composed of chromosome enumeration probes for 3, 7, 17 and a locus specific probe for 9p21/CDKN2A yielded a normal result (i.e. two copies per cell), favoring a primary versus metastatic melanocytic neoplasm of the CNS. We report a case in which the combination of mutational analysis and FISH aided in identifying the origin of the neoplasm.
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PMID:Is it a primary or metastatic melanocytic neoplasm of the central nervous system?: A molecular based approach. 2427 19


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