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)

The incidence of cutaneous melanoma is steadily increasing. Although several molecular abnormalities have been associated with melanoma progression, the mechanisms underlying the differential gene expression are still largely unknown and targeted therapies are not yet available. Noncoding small RNAs, termed microRNAs (miR), have been recently reported to play important roles in major cellular processes, including those involved in cancer development and progression. We have identified the promyelocytic leukemia zinc finger (PLZF) transcription factor as a repressor of miR-221 and miR-222 by direct binding to their putative regulatory region. Specifically, PLZF silencing in melanomas unblocks miR-221 and miR-222, which in turn controls the progression of the neoplasia through down-modulation of p27Kip1/CDKN1B and c-KIT receptor, leading to enhanced proliferation and differentiation blockade of the melanoma cells, respectively. In vitro and in vivo functional studies, including the use of antisense "antagomir" oligonucleotides, confirmed the key role of miR-221/-222 in regulating the progression of human melanoma; this suggests that targeted therapies suppressing miR-221/-222 may prove beneficial in advanced melanoma.
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PMID:The promyelocytic leukemia zinc finger-microRNA-221/-222 pathway controls melanoma progression through multiple oncogenic mechanisms. 1841 45

BRAF and NRAS are commonly mutated in cancer and represent the most frequent genetic events in malignant melanoma. More recently, a subset of melanomas was shown to overexpress KIT and harbor KIT mutations. Although most gastrointestinal stromal tumors (GISTs) exhibit activating mutations in either KIT or PDGFRA, about 10% of the cases lack mutations in these genes. It is our hypothesis following the melanoma model that mutations in BRAF or NRAS may play a role in wild-type GIST pathogenesis. Alterations in RAS/MEK/ERK pathway may also be involved in development of imatinib resistance in GIST, particularly in tumors lacking secondary KIT or PDGFRA mutations. Imatinib-naive wild-type GISTs from 61 patients, including 15 children and 28 imatinib-resistant tumors without secondary KIT mutations were analyzed. Screening for hot spots mutations in BRAF (exons 11 and 15) and NRAS (exons 2 and 3) was performed. A BRAF exon 15 V600E was identified in 3 of 61 GIST patients, who shared similar clinical features, being 49- to 55-years-old females and having their tumors located in the small bowel. The tumors were strongly KIT immunoreactive and had a high risk of malignancy. An identical V600E BRAF mutation was also identified in one of 28 imatinib resistant GIST lacking a defined mechanism of drug resistance. In conclusion, we identified a primary BRAF V600E mutations in 7% of adult GIST patients, lacking KIT/PDGFRA mutations. The BRAF-mutated GISTs show predilection for small bowel location and high risk of malignancy. A secondary V600E BRAF mutation could represent an alternative mechanism of imatinib resistance. Kinase inhibitors targeting BRAF may be effective therapeutic options in this molecular GIST subset.
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PMID:Novel V600E BRAF mutations in imatinib-naive and imatinib-resistant gastrointestinal stromal tumors. 1861 79

Although many melanomas harbor either activating mutations in BRAF or NRAS, there remains a substantial, yet little known, group of tumors without either mutation. Here, we used a genomic strategy to define a novel group of melanoma cell lines with co-overexpression of cyclin-dependent kinase 4 (CDK4) and KIT. Although this subgroup lacked any known KIT mutations, they had high phospho-KIT receptor expression, indicating receptor activity. Quantitative PCR confirmed the existence of a similar KIT/CDK4 subgroup in human melanoma samples. Pharmacologic studies showed the KIT/CDK4-overexpressing subgroup to be resistant to BRAF inhibitors but sensitive to imatinib in both in vitro and in vivo melanoma models. Mechanistically, imatinib treatment led to increased apoptosis and G(1) phase cell cycle arrest associated with the inhibition of phospho-ERK and increased expression of p27(KIP). Other melanoma cell lines, which retained some KIT expression but lacked phospho-KIT, were not sensitive to imatinib, suggesting that KIT expression alone is not predictive of response. We suggest that co-overexpression of KIT/CDK4 is a potential mechanism of oncogenic transformation in some BRAF/NRAS wild-type melanomas. This group of melanomas may be a subpopulation for which imatinib or other KIT inhibitors may constitute optimal therapy.
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PMID:Identification of a novel subgroup of melanomas with KIT/cyclin-dependent kinase-4 overexpression. 1863 27

MicroRNAs (miRNAs) represent a new family of small noncoding RNAs that negatively regulate gene expression. Recent studies demonstrated miRNA involvement in all the main biological processes, including tumor development as a consequence of an aberrant deregulated expression. Growing evidence is showing the capability of miRNA expression profiles to unequivocally distinguish between normal and neoplastic tissues, leading to the identification of new diagnostic and/or prognostic molecular markers. In addition, miRNAs might eventually represent new targets to aim at as innovative therapeutic approaches, particularly relevant in those types of cancer, such as melanoma, which are still lacking effective traditional therapies. In particular, the inhibition of miRNA-221 and -222, which are abnormally expressed in melanoma and favor the induction of the malignant phenotype by downregulating c-KIT receptor and p27Kip, might in the future represent an efficient treatment for translation into the clinical setting.
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PMID:MicroRNA-221 and -222 pathway controls melanoma progression. 1898 36

The article reviews the main molecular pathology alterations of endometrial and ovarian carcinomas and melanoma. Several promising drugs targeting the genes most frequently altered in these tumors are under consideration. The most promising signaling pathways to be targeted for therapies in these tumors are the tyrosine kinase receptor (EGFR, HER2, c-KIT), the RAS/B-RAF/MAPK, the PI3K-mTOR, and apoptosis signaling pathways.
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PMID:Targeted therapies in gynecologic cancers and melanoma. 1901 92

Recent studies showed KIT gene aberrations in a substantial number of melanomas on acral skin and mucosa, suggesting the therapeutic benefit of tyrosine kinase inhibitors, such as imatinib. We therefore examined the expression and mutations of KIT in 4 primary and 24 metastatic acral and mucosal melanomas. Immunohistochemistry revealed moderate or strong KIT protein expression in 13 (48%) tumors. Sequence analysis revealed K642E and D820Y mutations in two metastases. Amplification of KIT was identified by real-time PCR in 4 tumors, including one that had K642E. Western blot analysis showed phosphorylation of the KIT receptor in 8 (62%) of 13 cryopreserved samples, indicating the frequent pathological activation of the receptor in vivo. Phosphorylation of KIT protein was detected in 2 tumors harboring KIT mutations, as well as in one tumor with KIT gene amplification. Furthermore, 5 tumors without detectable KIT gene aberrations showed phosphorylation of the KIT receptor. Expression of stem cell factor (SCF) in melanoma cells as well as stromal cells suggests SCF/KIT autocrine and paracrine activation in these tumors. Finally, we found significant growth suppressive effects of sunitinib in two acral melanoma cell lines; one harboring the D820Y mutation and one showing SCF-dependent KIT activation. These results show pathological activation of KIT in a substantial number of metastatic tumors of acral and mucosal melanomas, and suggest a potential therapeutic benefit of sunitinib for these melanomas.
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PMID:Pathological activation of KIT in metastatic tumors of acral and mucosal melanomas. 1903 43

The hypo-pigmentation of human skin on the palms and the soles compared with other areas of the body has recently been reported to be due to mesenchymal-epithelial interactions via a fibroblast-derived factor, dickkopf 1, an inhibitor of the canonical Wnt signaling pathway. Recently, it has been reported that keratinocytes play a significant role in skin color determination by producing cytokines involved in melanogenesis. Thus, we hypothesized that the downregulated expression of keratinocyte- or fibroblast-derived melanogenic cytokines may also be responsible for the decreased function of palmoplantar (PP) melanocytes in addition to the suppressive effects of dickkopf 1 on melanogenic function in epidermal melanocytes. Immunohistochemistry revealed that the number of tyrosinase, S100alpha, c-KIT, endothelin B receptor (ETBR), SOX10, and microphthalmia-associated transcription factor (MITF) immuno-positive melanocytes is significantly reduced in PP epidermis. In contrast, dopa-histochemistry demonstrated no substantial reduction in melanocyte populations in PP epidermis. Real-time RT-PCR revealed that the expression of stem cell factor (SCF) and endothelin (ET)-1 mRNAs in PP skin was significantly downregulated. In parallel, immunohistochemistry revealed that SCF and ET-1 immuno-staining was markedly attenuated in PP skin. Western blotting revealed that the expression of SCF, c-KIT, and MITF-M proteins was significantly decreased in PP skin. These findings suggest the possibility that downregulation of ET-1/SCF/receptor linkages is also associated with the decreased function of melanocytes in PP skin.
Pigment Cell Melanoma Res 2008 Dec
PMID:Downregulated melanogenic paracrine cytokine linkages in hypopigmented palmoplantar skin. 1908 31

News in the oncodermatology field this year were dominated by publications treating of melanoma and concerning in particular our increased knowledge of the various biological pathways involved in the distinct subtypes of melanoma. This molecular diversity is probably one of the reasons explaining the poor results of most of the clinical trials recently published because we don't know yet how to identify and select the right population of patients who could beneficiate from such or such therapy. However, some very encouraging results obtained with new protocols for adoptive immunotherapy have been published and we also hope that further results will confirm that the subset of KIT-mutated melanomas will beneficiate from an efficient targeted anti-Kit therapy. Besides melanoma, the scoop of the year was the discovery of a defective oncogenic polyomavirus which is very likely to be responsible for Merkel cell carcinoma.
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PMID:[What is new in oncodermatology?]. 1926 11

A tumor suppressor gene at 10q23.3, designated PTEN, encoding a dual-specificity phosphatase with lipid and protein phosphatase activity, has been shown to play a pivotal role in the pathogenesis of a variety of human cancers. A frequent loss of heterozygosity (LOH) at 10q is found in melanoma; however, little is known about the role of PTEN in the pathogenesis of a primary malignant melanoma derived from ovarian mature cystic teratoma, which is an extremely rare melanoma. This study examined the genetic alterations involved in the mitogen-activated protein kinase and phosphatidylinositol 3 kinase pathways in an ovarian malignant melanoma. A LOH analysis revealed hemizygous deletion around and in the PTEN gene not only in the ovarian melanoma but also in a mature cystic teratoma. Another case of ovarian mature cystic teratomas in the absence of melanoma also showed allelic loss of the PTEN region. To date, mutations of BRAF, NRAS, and KIT genes have been reported in malignant melanomas. In the present study, D816H and K558E mutations of the KIT gene were revealed in the melanoma arising from a mature cystic teratoma, but not in a mature cystic teratoma. No mutations of the BRAF and NRAS genes were found in the melanoma. These results indicate that LOH of the PTEN region is one of the molecular alterations of an ovarian mature cystic teratoma and a KIT mutation is an additional promotional event associated with the oncogenesis of a melanoma arising from an ovarian mature cystic teratoma.
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PMID:Mutations of the KIT gene and loss of heterozygosity of the PTEN region in a primary malignant melanoma arising from a mature cystic teratoma of the ovary. 1926 28

As we enter the era of targeted therapy for melanoma, attempts are being made to sub-group tumors on the basis of their driving oncogenic mutations, with the hope of developing truly personalized therapeutic regimens. c-KIT is a receptor tyrosine kinase whose aberrant activation is implicated in the progression of gastrointestinal stromal tumors and some acute myeloid leukemias. The role of c-KIT signaling in melanoma has been controversial; although c-KIT activity is critical to melanocyte development, its expression tends to be lost in most melanomas. Some reports have even shown that the re-expression of c-KIT induces apoptosis in melanoma cell lines. The recent publication of work showing the presence of activating c-KIT mutations in acral and mucosal melanomas, as well as melanomas arising on skin with chronic sun damage, has renewed interest in c-KIT signaling in melanoma. Recent work from our own laboratory has further identified melanomas with constitutive c-KIT signaling activity resulting from c-KIT receptor overexpression. Although the initial clinical trials of the c-KIT inhibitor imatinib mesylate in melanoma were negative, some dramatic responses have been seen in patients with very high c-KIT expression and/or documented activating mutations, fostering the belief that focused studies in patients selected on the basis of c-KIT mutational status will yield more encouraging results. The current review discusses the role of c-KIT signaling in melanoma progression and how this new information can be applied to the targeted therapy of melanoma.
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PMID:c-KIT signaling as the driving oncogenic event in sub-groups of melanomas. 1928 71


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