Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oncogenic BRAF as an early and fundamental feature of melanocytic neoplasia has been confirmed with its identification in both melanoma and nevi. Oncogenic BRAF has been shown to induce senescence/apoptosis by up-regulating the tumor suppressor IGFBP7, which acts through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling. Given the putative neoplastic potential of dysplastic nevi, our aim was to ascertain in dysplastic nevi from intermittently sun-exposed skin and of varying severity the frequency of oncogenic BRAF and NRAS and to assess expression of IGFBP7 in the same. BRAF and NRAS genotyping was performed on genomic DNA (isolated using laser capture microdissection) from dysplastic nevi ranging in severity from mild (12), to moderate (11), and to severe (11). Immunohistochemical staining for IGFBP7 was performed on all. Overall, 9 (26%) of 34 cases (2 severely atypical dysplastic nevi, 2 moderately atypical dysplastic nevi, and 5 mildly atypical dysplastic nevi) exhibited the BRAFV600E mutation (P = .22), with lack of IGFBP7 expression in 4 (44.4%) of 9 cases (1 severely atypical, 1 moderately atypical, and 2 mildly atypical); and 25 (73.5%) of 34 cases (9 severely atypical, 9 moderately atypical, and 7 mildly atypical) were BRAFWT, with enhanced IGFBP7 expression in 12 (48%) of 25 cases (6 severely atypical, 3 moderately atypical, and 3 mildly atypical). All cases were NRASWT. The disparate expression of IGFBP7 in BRAFV600E-positive dysplastic nevi (enhanced in 56% and diminished/absent in 44%) indicates that the behavior of oncogenic BRAF in dysplastic nevi, unlike that in malignant melanoma, does not appear to consistently induce senescence/apoptosis through pathways mediated by IGFBP7.
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PMID:Oncogenic BRAF-positive dysplastic nevi and the tumor suppressor IGFBP7--challenging the concept of dysplastic nevi as precursor lesions? 2023 23

Cultured human melanocytes are increasingly being used in the treatment of vitiligo. The growth media contain various types of mitogenic factors, both recombinant human (e.g., rhbFGF and rhSCF) and synthetic (e.g., TPA). High concentrations of mitogenic factors accelerate the cell cycle, and consequently may increase the risk of carcinogenesis of transplanted cells. Mutations of genes of the RAS/RAF/MEK/ERK signaling pathway are very often found in the early stages of the development of melanoma. TPA is considered to be an oncogenic factor, but so far there is no evidence to show that it is responsible for damage to the genetic material of cultured melanocytes. The aim of our study was to assess the risk of the development of mutations in selected genes of the RAS/RAF/MEK/ERK signaling pathway during the culturing of melanocytes in various growth media. Based on the results obtained, it can be concluded that TPA and high concentrations of other growth factors intensify the proliferation of melanocytes, without the risk of damage to the HRAS (exon 1 and 2), KRAS (exon 1 and 2), NRAS (exon 1 and 2), and BRAF (exon 11 and 15) genes. In order to assess the total safety of the transplantation of cultured melanocytes, it is necessary to carry out further studies on other signaling pathways as well as carry out biological tests on an animal model.
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PMID:Transplantation of cultured autologous melanocytes: hope or danger? 2035 Mar 53

Malignant cutaneous melanoma is a highly aggressive form of skin cancer. Despite improvements in early melanoma diagnosis, the 5-year survival rate remains low in advanced disease. Therefore, novel biomarkers are urgently needed to devise new means of detection and treatment. In this study, we aimed to improve our understanding of microRNA (miRNA) deregulation in melanoma development and their impact on patient survival. Global miRNA expression profiles of a set of melanoma lymph node metastases, melanoma cell lines, and melanocyte cultures were determined using Agilent array. Deregulated miRNAs were evaluated in relation with clinical characteristics, patient survival, and mutational status for BRAF and NRAS. Several miRNAs were differentially expressed between melanocytes and melanomas as well as melanoma cell lines. In melanomas, miR-193a, miR-338, and miR-565 were underexpressed in cases with a BRAF mutation. Furthermore, low expression of miR-191 and high expression of miR-193b were associated with poor melanoma-specific survival. In conclusion, our findings show miRNA dysregulation in malignant melanoma and its relation to established molecular backgrounds of BRAF and NRAS oncogenic mutations. The identification of an miRNA classifier for poor survival may lead to the development of miRNA detection as a complementary prognostic tool in clinical practice.
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PMID:MicroRNA expression profiles associated with mutational status and survival in malignant melanoma. 2035 17

Resistance of cancer cells to apoptosis is dependent on a balance of multiple genetic and epigenetic mechanisms, which up-regulate efficacy of the surviving growth factor-receptor signaling pathways and suppress death-receptor signaling pathways. The Insulin-like Growth Factor-1 Receptor (IGF-1R) signaling pathway is highly active in metastatic melanoma cells by mediating downstream activation of PI3K-AKT and MAPK pathways and controlling general cell survival and proliferation. In the present study, we used human melanoma lines with established genotypes that represented different phases of cancer development: radial-growth-phase WM35, vertical-growth-phase WM793, metastatic LU1205 and WM9 [1]. All these lines have normal NRAS. WM35, WM793, LU1205 and WM9 cells have mutated BRAF (V600E). WM35 and WM9 cells express normal PTEN, while in WM793 cells PTEN expression is down-regulated; finally, in LU1205 cells PTEN is inactivated by mutation. Cyclolignan picropodophyllin (PPP), a specific inhibitor of IGF-1R kinase activity, strongly down-regulated the basal levels of AKT activity in WM9 and in WM793 cells, modestly does so in LU1205, but has no effect on AKT activity in the early stage WM35 cells that are deficient in IGF-1R. In addition, PPP partially down-regulated the basal levels of active ERK1/2 in all lines used, highlighting the role of an alternative, non-BRAF pathway in MAPK activation. The final result of PPP treatment was an induction of apoptosis in WM793, WM9 and LU1205 melanoma cells. On the other hand, dose-dependent inhibition of IGF-1R kinase activity by PPP at a relatively narrow dose range (near 500 nM) has different effects on melanoma cells versus normal cells, inducing apoptosis in cancer cells and G2/M arrest of fibroblasts. To further enhance the pro-apoptotic effects of PPP on melanoma cells, we used a combined treatment of TNF-Related Apoptosis-Inducing Ligand (TRAIL) and PPP. This combination substantially increased death by apoptosis for WM793 and WM9 cells, but did so only modestly for LU1205 cells with very high basal activity of AKT. The ultimate goal of this direction of research is the discovery of a new treatment method for highly resistant human metastatic melanomas. Our findings provide the rationale for further preclinical evaluation of this novel treatment.
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PMID:Disruption of IGF-1R signaling increases TRAIL-induced apoptosis: a new potential therapy for the treatment of melanoma. 2041

We have developed a somatic cell gene delivery mouse model of melanoma that allows for the rapid validation of genetic alterations identified in this disease. A major advantage of this system is the ability to model the multi-step process of carcinogenesis in immune-competent mice without the generation and cross breeding of multiple strains. We have used this model to evaluate the role of RAS isoforms in melanoma initiation in the context of conditional Ink4a/Arf loss. Mice expressing the tumor virus A (TVA) receptor specifically in melanocytes under control of the dopachrome tautomerase (DCT) promoter were crossed to Ink4a/Arf(lox/lox) mice and newborn DCT-TVA/Ink4a/Arf(lox/lox) mice were injected with retroviruses containing activated KRAS, NRAS and/or Cre-recombinase. No mice injected with viruses containing KRAS and Cre or NRAS alone developed tumors; however, more than one-third of DCT-TVA/Ink4a/Arf(lox/lox) mice injected with NRAS and Cre viruses developed melanoma and two-thirds developed melanoma when NRAS and Cre expression was linked.
Pigment Cell Melanoma Res 2010 Aug
PMID:Targeted delivery of NRASQ61R and Cre-recombinase to post-natal melanocytes induces melanoma in Ink4a/Arflox/lox mice. 2044 98

The small G-protein NRAS is mutated in 22% of human melanomas, whereas the related proteins KRAS and HRAS are mutated in only 2% and 1% of melanomas, respectively. We have developed a mouse model of melanoma in which Cre recombinase/LoxP technology is used to drive inducible expression of (G12V)KRAS in the melanocytic lineage. The mice develop skin hyperpigmentation, nevi, and tumors that bear many of the cardinal histopathology features and molecular characteristics of human melanoma. These tumors invade and destroy the underlying muscles and cells derived from them can grow as subcutaneous tumors and colonize the lungs of nude mice. These data establish that oncogenic KRAS can be a founder event in melanomagenesis.
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PMID:A mouse model of melanoma driven by oncogenic KRAS. 2051 23

We performed DNA microarray-based comparative genomic hybridization to identify somatic alterations specific to melanoma genome in 60 human cell lines from metastasized melanoma and from 44 corresponding peripheral blood mononuclear cells. Our data showed gross but nonrandom somatic changes specific to the tumor genome. Although the CDKN2A (78%) and PTEN (70%) loci were the major targets of mono-allelic and bi-allelic deletions, amplifications affected loci with BRAF (53%) and NRAS (12%) as well as EGFR (52%), MITF (40%), NOTCH2 (35%), CCND1 (18%), MDM2 (18%), CCNE1 (10%), and CDK4 (8%). The amplified loci carried additional genes, many of which could potentially play a role in melanoma. Distinct patterns of copy number changes showed that alterations in CDKN2A tended to be more clustered in cell lines with mutations in the BRAF and NRAS genes; the PTEN locus was targeted mainly in conjunction with BRAF mutations. Amplification of CCND1, CDK4, and other loci was significantly increased in cell lines without BRAF-NRAS mutations and so was the loss of chromosome arms 13q and 16q. Our data suggest involvement of distinct genetic pathways that are driven either through oncogenic BRAF and NRAS mutations complemented by aberrations in the CDKN2A and PTEN genes or involve amplification of oncogenic genomic loci and loss of 13q and 16q. It also emerges that each tumor besides being affected by major and most common somatic genetic alterations also acquires additional genetic alterations that could be crucial in determining response to small molecular inhibitors that are being currently pursued.
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PMID:Somatic alterations in the melanoma genome: a high-resolution array-based comparative genomic hybridization study. 2054 47

Up to one-third of human melanomas are characterized by an oncogenic mutation in the gene encoding the small guanosine triphosphatase (GTPase) NRAS. Ras proteins activate three primary classes of effectors, namely, Rafs, phosphatidyl-inositol-3-kinases (PI3Ks) and Ral guanine exchange factors (RalGEFs). In melanomas lacking NRAS mutations, the first two effectors can still be activated through an oncogenic BRAF mutation coupled with a loss of the PI3K negative regulator PTEN. This suggests that Ras effectors promote melanoma, regardless of whether they are activated by oncogenic NRas. The only major Ras effector pathway not explored for its role in melanoma is the RalGEF-Ral pathway, in which Ras activation of RalGEFs converts the small GTPases RalA and RalB to an active guanosine triphosphate-bound state. We report that RalA is activated in several human melanoma cancer cell lines harboring an oncogenic NRAS allele, an oncogenic BRAF allele or wild-type NRAS and BRAF alleles. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of RalA, and to a lesser extent of RalB, variably inhibited the tumorigenic growth of melanoma cell lines having these three genotypes. Thus, as is the case for Raf and PI3 K signaling, Rals also contribute to melanoma tumorigenesis.
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PMID:Ral activation promotes melanomagenesis. 2056 21

The p16(INK4A) tumor suppressor is often deleted, or otherwise inactivated, in malignant melanoma. To investigate the loss of p16(INK4A) in greater detail, we analyzed 77 cutaneous melanoma metastases. Of these 56 retained at least one p16(INK4A) allele, and 21 had biallelic deletions. Using methylation-specific PCR, direct sequencing, and immunohistochemical methods, we analyzed p16(INK4A) promoter methylation, mutations, and protein expression, respectively. In addition, 14 corresponding primary tumors were analyzed for protein expression. Results were compared to clinicopathological parameters and previously obtained data regarding mutations in proto-oncogenes NRAS and BRAF. Results revealed that p16(INK4A) promoter methylation was present in 15 of 59 (25%) metastases; nonsynonymous mutations in 9 of 56 (16%) metastases; and protein expression in 12 of 67 (18%) metastases. Protein expression was lost during progression from primary to metastatic tumors, 71% (10 of 14) and 43% (6 of 14) being positive, respectively. However, the genetic and epigenetic alterations of p16(INK4A) observed could not explain the lack of p16(INK4A) protein in 27 metastases, indicating the presence of additional inactivating mechanisms for p16(INK4A). Interestingly, p16(INK4A) promoter methylation was significantly overrepresented in NRAS-mutated samples compared to NRAS wild-type samples (P=0.0004), indicating an association between these two events.
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PMID:High frequency of p16(INK4A) promoter methylation in NRAS-mutated cutaneous melanoma. 2070 44

Melanoma is comprised of biologically distinct subtypes. The defining clinical, histomorphologic, and molecular features are not fully established. This study sought to validate the association between genetic and histomorphologic features previously described and to determine their reproducibility and association with important clinical variables. Detailed clinical and histomorphologic features of 365 primary cutaneous melanomas were assessed by 11 pathologists and correlated with mutation status of BRAF and NRAS. There was substantial agreement in the quantitative assessment of histomorphologic features showing similar or better interobserver reproducibility than the established World Health Organization classification scheme. We confirmed that melanomas with BRAF mutations showed characteristic morphologic features (P < 0.0001) and metastasized more frequently to regional lymph nodes (P = 0.046). Importantly, melanomas without mutations were a heterogeneous group, with a subset having very similar clinical and morphological features as those with BRAF mutation raising the possibility that they are biologically related. Our study confirms an association between histomorphologic features, mutation status, and pattern of metastasis, providing criteria for a refined melanoma classification aimed at defining biologically homogeneous disease subgroups.
Pigment Cell Melanoma Res 2010 Dec
PMID:Genetic and morphologic features for melanoma classification. 2087 33


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