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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanoma cells have surface markers that are expressed differently than in normal melanocytes and nevus cells. Monoclonal antibodies may define a phenotypic map of the various melanocytic lesions and can be used in immunohistopathology and immunoscintigraphy. Monoclonal antibodies directed against melanoma-associated glycoproteins and glycolipids are being tested for therapy. Rearrangements or deletions on chromosome 1, 6, and 7 are the most frequently observed cytogenetic abnormalities. Molecular studies have not given a clear picture. A subset of HRAS alleles has been reported to be associated with melanoma. NRAS activation by point mutation has been found in one fourth of the cases. Allele losses at different loci have been reported. Genetic linkage studies have given conflicting results on the presence of a gene for the melanoma-dysplastic nevus syndrome on the short arm of chromosome 1.
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PMID:Cellular and molecular biology of melanoma. 143 44

Three methods to detect single base mutations in codon 61 of the human NRAS gene from human melanoma DNA are described and compared: oligonucleotide hybridization analysis and direct manual and automated sequence analysis. Point mutations are detected by oligonucleotide hybridization and direct manual and direct automated sequence analysis of in vitro amplified genomic DNA. Heterozygosity for mutant alleles is reliably detected by oligonucleotide hybridization and by direct manual, but not by direct automated, sequence analysis. Generating single-stranded DNA via "asymmetric polymerase chain reaction (PCR)" and utilizing alpha 35S-dATP as radiolabel for manual sequencing and fluorescent-dye labeled primers for automated sequencing (Applied Biosystems, Inc.), we can obtain sequence information from either strand. The use of several of these methodologies to detect single base changes in the human NRAS gene is illustrated. In addition, the use of these and other related techniques to define the involvement of RAS oncogenes in human melanomas more precisely is reviewed.
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PMID:Mutational analysis of human NRAS genes in malignant melanoma: rapid methods for oligonucleotide hybridization and manual and automated direct sequencing of products generated by the polymerase chain reaction. 227 57

Activation of certain oncogenes may alter the sensitivity of cells to ionizing radiation. We studied the effect of oncogene activation on the radiation sensitivity of cells of a human melanoma cell line. The cell line IGR39D was transfected with the MYC oncogene, the proto-oncogene NRAS, NRAS activated by a point mutation (61-arginine) or a combination of mutated NRAS and MYC. Single-dose experiments showed a decreased survival after transfection with MYC, wild-type NRAS or mutated NRAS. Co-transfection with MYC and mutated NRAS decreased survival up to 4 Gy, whereas at higher doses no shift in radiosensitivity was seen. Flow cytometry data indicated that differences in radiosensitivity could be explained at least in part by a difference in the distribution of cells in the phases of the cell cycle. After transfection of cells with either NRAS or MYC, the number of cells in G1 phase decreased with a concomitant increase of cells in the G2/M phase. When the cell line transfected with activated NRAS was manipulated so that the distribution of the cells in the phases of the cell cycle resembled th at of the parental line at the time of irradiation, the survival of the cells was improved. Similar experiments with the cell line containing MYC did not result in an alteration of the distribution of the cells in the cycle, or the survival after single-dose fractions, suggesting the presence of a distinct mechanism for influencing radiation sensitivity. Both NRAS and MYC transfection decrease the radiation sensitivity of human melanoma cells, but the underlying mechanisms seem different. In conclusion, transfection with NRAS or MYC alone increases radiation sensitivity while transfection of cells containing NRAS with MYC restores resistance at higher doses.
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PMID:The influence of the oncogenes NRAS and MYC on the radiation sensitivity of cells of a human melanoma cell line. 892 9

BRAF is a serine/threonine kinase that receives a mitogenic signal from RAS and transmits it to the MAP kinase pathway. Recent studies have reported that mutations of the BRAF gene were detected with varying frequencies in several cancers, notably more than 60% in melanoma. We analysed mutations of BRAF and RAS genes in 100 cases of thyroid carcinoma to investigate genetic aberrations in the RAS/RAF/MEK/MAP kinase pathway. BRAF mutations were detected exclusively in papillary carcinomas (40 in 76 cases: 53%), and were exclusively V599E, a mutation frequently observed in other carcinomas. NRAS mutation was observed in six cases (6%), all in histological types other than papillary carcinoma, and was exclusively Q61R. No mutations were found in KRAS or HRAS. Our results suggest that BRAF mutations may play a critical role in the carcinogenesis of papillary carcinoma of the thyroid.
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PMID:BRAF mutations in papillary carcinomas of the thyroid. 1450 25

Uveal melanoma (UM) and cutaneous melanoma (CM) differ significantly in their epidemiological, clinical, immunophenotypical, and cytogenetic features, but the molecular basis for these differences has not been delineated. CMs frequently harbor an activating mutation in either NRAS or the RAS-regulated kinase BRAF, suggesting that either of these oncogenes may increase signaling through the mitogen-activated protein (MAP) kinase pathway and promote melanoma development. The aim of this study was to examine BRAF and NRAS gene mutations in UM. Genomic DNA from CM and UM was screened for mutations in BRAF exons 11 and 15 and NRAS exons 1 and 2 using a combination of denaturing high-performance liquid chromatography and direct sequencing. Mutations in BRAF exon 15 were detected in 16 (36.4%) of 44 CMs and 0 (0%) of 62 UMs. The most common mutation in CM was V599E, but a novel point mutation (L596Q) was identified in two cases and an in-frame deletion/insertion (VKSRWK599-604D) was discovered in one case. No BRAF exon 11 mutations were observed among seven CMs and nine UMs that were wild-type for exon 15. Mutation of NRAS exon 2 was rare in CM [1 (3.7%) of 27] and absent in UM [0 (0%) of 47]. No NRAS exon 1 mutations were detected in either type of melanoma. We conclude that UMs arise independent of oncogenic BRAF and NRAS mutations, an observation that may have implications for therapies targeted to the NRAS-BRAF pathway.
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PMID:Absence of BRAF and NRAS mutations in uveal melanoma. 1452 97

Ras signaling is important for the intracellular transduction of mitogenic stimuli from activated growth factor receptors. We have investigated 37 sporadic malignant melanomas (15 primary cutaneous melanomas and 22 melanoma metastases) and 6 melanoma cell lines for mutations in the 3 Ras genes NRAS, KRAS and HRAS. All tumors and cell lines were additionally analyzed for mutation and expression of BRAF, which encodes a Ras-regulated serine/threonine kinase with oncogenic properties, as well as for expression of RASSF1A, which encodes a Ras-binding protein with tumor suppressor properties. Mutational analyses identified somatic NRAS mutations in 2 primary melanomas, 4 melanoma metastases and 2 cell lines. One melanoma metastasis showed a somatic KRAS mutation whereas HRAS mutations were not detected. Eight primary melanomas, 6 melanoma metastases and 4 melanoma cell lines carried BRAF mutations affecting the known hot-spot codon 599. None of the tumors or cell lines with BRAF mutation demonstrated NRAS or KRAS mutations. Real-time reverse transcription-PCR showed that 8 melanomas (3 primary tumors, 5 melanoma metastases) had reduced RASSF1A transcript levels of < or =50% relative to benign melanocytic nevi and normal skin. Three melanoma cell lines lacked detectable RASSF1A transcripts. The RASSF1A gene promoter was hypermethylated in these 3 cell lines as well as in 6 of 8 melanomas with reduced RASSF1A mRNA levels. Treatment of the cell lines with 5-aza-2'-deoxycytidine and trichostatin A resulted in demethylation of the RASSF1A promoter and re-expression of RASSF1A transcripts. Most tumors and all cell lines with RASSF1A promoter methylation additionally carried BRAF or NRAS mutations, suggesting a synergistic effect of these aberrations on melanoma growth. Taken together, 57% of the investigated melanomas and 100% of the melanoma cell lines carried mutations in either NRAS, KRAS or BRAF. In addition, 22% of the melanomas and 50% of the cell lines showed reduced RASSF1A transcript levels. Thus, alterations of Ras pathway genes are of paramount importance in the pathogenesis of sporadic melanomas.
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PMID:Frequent alterations of Ras signaling pathway genes in sporadic malignant melanomas. 1496 76

Extant evidence implicates growth factor signaling in the pathogenesis of many tumor types, including cutaneous melanoma. Recently, reciprocal activating mutations of NRAS and BRAF were found in benign melanocytic nevi and cutaneous melanomas. We had previously reported a similar epistatic relationship between activating NRAS mutations and inactivating PTEN/MMAC1 alterations. We thus hypothesized that BRAF and PTEN/MMAC1 mutations may cooperate to promote melanoma tumorigenesis. Overall, 40 of 47 (85%) melanoma cell lines and 11 of 16 (69%) uncultured melanoma metastases had mutations in NRAS, BRAF, or PTEN/MMAC1. NRAS was exclusively mutated in nine of 47 (19%) cell lines and two of 16 (13%) metastases, whereas BRAF was solely mutated in 28 of 47 (60%) cell lines and nine of 16 (56%) metastases. In the 12 of 15 melanoma cell lines (80%) and two of two melanoma metastases with PTEN alterations, BRAF was also mutated. These findings suggest the existence of possible cooperation between BRAF activation and PTEN loss in melanoma development.
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PMID:Genetic interaction between NRAS and BRAF mutations and PTEN/MMAC1 inactivation in melanoma. 2183 10

We have used microarray gene expression profiling and machine learning to predict the presence of BRAF mutations in a panel of 61 melanoma cell lines. The BRAF gene was found to be mutated in 42 samples (69%) and intragenic mutations of the NRAS gene were detected in seven samples (11%). No cell line carried mutations of both genes. Using support vector machines, we have built a classifier that differentiates between melanoma cell lines based on BRAF mutation status. As few as 83 genes are able to discriminate between BRAF mutant and BRAF wild-type samples with clear separation observed using hierarchical clustering. Multidimensional scaling was used to visualize the relationship between a BRAF mutation signature and that of a generalized mitogen-activated protein kinase (MAPK) activation (either BRAF or NRAS mutation) in the context of the discriminating gene list. We observed that samples carrying NRAS mutations lie somewhere between those with or without BRAF mutations. These observations suggest that there are gene-specific mutation signals in addition to a common MAPK activation that result from the pleiotropic effects of either BRAF or NRAS on other signaling pathways, leading to measurably different transcriptional changes.
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PMID:Microarray expression profiling in melanoma reveals a BRAF mutation signature. 1504 78

To elucidate the biological significance of activating mutations of BRAF in human malignant tumors, we performed a mutation analysis using 43 cell lines established from tumors that had developed in several kinds of human organs. Because the same V599E point mutation was observed in three of six melanoma cell lines and no such mutations were observed in other types of cancers, we focused further on melanoma, performed mutation analyses of NRAS, KRAS, CTNNB1, and p16/p14(ARF) in these cell lines, and found one NRAS mutation and three p16/p14(ARF) mutations. We further searched for mutations of BRAF and NRAS in 35 primary sporadic melanomas from 35 Japanese patients and detected the V599E BRAF point mutation in only nine (26%) of them. Significant differences in mutation frequency were observed among four histological subtypes; four (50%) of eight superficially spreading melanoma and five (33%) of 15 acral lentiginous melanoma had the mutation, whereas none of 12 other types (six nodular melanoma, five lentigo melanoma, and one mucosal melanoma) had it. The BRAF mutation was observed frequently even in small lesions, indicating that activation of this gene may be one of the early events in the pathogenesis of some melanomas.
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PMID:BRAF point mutations in primary melanoma show different prevalences by subtype. 1519 58

To evaluate the mutational profiles associated with BRAF mutations in human melanoma, we have studied BRAF, RAS, PTEN, TP53, CDKN2A and CDK4 genes and their expression in melanoma lesions. Owing to the lack of sufficient material from fresh specimens, we employed short-term cell lines obtained from melanoma biopsies. In all, 41 melanoma obtained from eight primary lesions, 20 nodal, 11 cutaneous and two visceral metastases from patients with sporadic (n=31), familial (n=4) and multiple melanoma (n=2) were analysed. The results revealed novel missense mutations in the BRAF, PTEN, CDKN2A and CDK4 genes. Overall, activating mutations of BRAF and loss of functional p16 and ARF were detected in the majority of melanomas (29/41, 36/41 and 29/41, respectively), while PTEN alterations/loss, NRAS and TP53 mutations occurred less frequently (6/41, 6/41 and 10/41, respectively). In the resulting 12 mutational profiles, p16/ARF loss associated with mutated BRAFV599E was the most represented (n=15). In addition, TP53 and PTEN mutations were always accompanied with BRAF alterations, while PTEN loss was found in association with CDKN2A or TP53 mutations in the absence of BRAF activation. The p16/ARFDelta+BRAF/RAS profile was significantly associated with a longer survival, while complex mutational profiles were detected in highly aggressive disease and poor survival. These data support the existence of several molecularly defined melanoma groups which likely reflect different clinical/biological behaviour, thus suggesting that a more extensive molecular classification of melanoma would significantly impact its clinical management.
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PMID:BRAF alterations are associated with complex mutational profiles in malignant melanoma. 1519 37


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