Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Malignant melanoma, a potentially lethal skin neoplasm, is characterized by a complex and heterogeneous etiology. Both incidences and deaths associated with melanoma are increasing in Caucasian populations. While exposure to ultraviolet radiation through sun-exposure is the major risk factor; the host factors including skin type and number of moles are critical in predisposition. The CDKN2A is a high penetrance melanoma susceptibility gene as carriers of the mutations are predisposed to the disease within familial settings. The gene is also somatically altered to varying degrees in sporadic melanoma. The CDK4 gene due to occurrence of activation mutations in a few families worldwide represents another melanoma susceptibility locus. The variants within the melanocortin receptor 1 (MC1R) gene, which encodes a melanocyte specific surface receptor with a key role in pigmentation, are associated with high risk phenotypes and increased risk of melanoma. Melanoma tumors are characterized by activation of the RAS-RAF-MEK-ERK pathway through either autocrine growth factor stimulation or oncogenic mutations in the B-RAF or N-RAS genes. Somatic mutations in the B-RAF gene are complemented by those in the N-RAS gene and represent the major genetic alterations. The mutations in the B-RAF gene in melanoma due to occurrence in melanocytic nevi represent early events that additionally require loss of cell cycle inhibitors like CDKN2A for melanoma progression and development. The sequence of events points to the cooperative collaboration between different genetic pathways in tumor development that can be and are being used as targets for developing specific therapeutic agents.
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PMID:Malignant melanoma--a genetic overview. 2009 96

Nevus of Ota is a variant of congenital nevus, which is morphologically paucicellular and resembles a common blue nevus. Although nevus of Ota is a risk factor for uveal melanoma in white people, the development of cutaneous melanoma within nevus of Ota is a very rare occurrence with only a few reported cases. We present a case of a long-standing nevus of Ota, with radiologic imaging demonstrating a large retro-orbital mass and a biopsy showing melanoma. The histopathology of the eye exenteration specimen illustrated various stages of melanocytic progression including areas resembling a nevus of Ota, blue nevus, cellular blue nevus, and melanoma. There was heterogeneity in the overtly malignant sections with some areas displaying expansile nodules of blander appearing spindled cells, whereas other areas were composed of epithelioid cells with higher mitotic counts and zones of necrosis. The extensive lesion also infiltrated the soft tissue and bone. We performed gene mutation analysis for GNAQ, BRAF, NRAS, and KIT and fluorescence in situ hybridization (FISH) targeting commonly altered chromosomal loci in melanoma and comparative genomic hybridization (CGH). Copy number changes typical of melanoma were identified by both FISH and CGH in the morphologically malignant areas illustrating the relationship of tumor progression and the progressive acquisition of genetic aberrations.
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PMID:Molecular analysis of a case of nevus of ota showing progressive evolution to melanoma with intermediate stages resembling cellular blue nevus. 2011 Jul 97

The macromonomer of 2-hydroxyethyl methyacrylate-caprolactone (HPCL) was synthesized by the ring-opening polymerization (ROP) of epsilon-caprolactone, which was initiated by 2-hydroxyethyl methyacrylate (HEMA). Then, the graft terpolymers of NIPAAm-co-AAc-co-HEMA-g-PCL (PHNA-CL) with varying mole ratios were subsequently synthesized by free radical polymerization of HEMA-PCL, N-isopropylacrylamide (NIPAAm) and acrylic acid (AAc). PHNA-CL was further self-assembled in different types of solvent. All the as-prepared copolymers were characterized by 1H NMR, FT-IR and GPC. Micellization behaviors of micelles were studied by TEM and DLS. The micelles exhibited a phase transition temperature which can be readily adjusted by changing pH value of the micellization system. Micelle loaded with doxorubicin (DOX) was used to evaluate the drug release behavior. The release of DOX from micelles could be controlled by changing pH value and temperature in buffer solutions. The micelles are potentially to be used as a new anticancer drug carrier for intracellular delivery.
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PMID:The pH-induced thermosensitive poly (NIPAAm-co-AAc-co-HEMA)-g-PCL micelles used as a drug carrier. 2021 89

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

FGFR3 mutations have recently been identified in several benign epidermal skin lesions such as seborrheic keratosis, epidermal nevus and solar lentigo. The functional consequences of these mutations in human skin are as yet unknown. In this study we analyzed the functional effects of the most common FGFR3 mutation in benign skin tumors, the R248C FGFR3 hotspot mutation, in human HaCaT keratinocytes. The cells were stably transduced with either the R248C or wildtype FGFR3 IIIb cDNA using a retroviral vector system. FGFR3 mutant and wildtype cells showed similar growth rates at subconfluence. However, at confluence FGFR3 mutant keratinocytes revealed a significantly higher cell number than wildtype cells. Furthermore, FGFR3 mutant cells showed significantly lower levels of apoptosis and decreased attachment to fibronectin compared with FGFR3 wildtype cells. Expression of mutant FGFR3 did not alter migration and senescence. Microarray analysis revealed only a few differentially expressed genes between FGFR3 mutant and wildtype keratinocytes. Enhanced phosphorylation of ERK1/2 was observed in confluent R248C mutant HaCaT cells compared with wildtype keratinocytes. Our results suggest that an increased cell number at confluence along with a decreased apoptosis may contribute to the development of acanthotic tumors in FGFR3 mutant skin in vivo.
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PMID:FGFR3 mutation affects cell growth, apoptosis and attachment in keratinocytes. 2042 Aug 24

It is the purpose of this review to extend our understanding of the fibroblast growth factor (FGF) receptor-2b-signaling network in the pathogenesis of acne. A new concept of the role of FGFR2b-signaling in dermal-epithelial interaction for skin appendage formation, pilosebaceous follicle homeostasis, comedogenesis, sebaceous gland proliferation and lipogenesis is presented. The FGFR2-gain-of-function mutations in Apert syndrome and unilateral acneiform nevus are most helpful model diseases pointing the way to androgen-dependent dermalepithelial FGFR2-signaling in acne. Androgen-mediated upregulation of FGFR2b-signaling in acne-prone skin appears to be involved in the pathogenesis of acne vulgaris. In organotypic skin cultures, keratinocyte-derived interleukin-1alpha stimulated fibroblasts to secrete FGF7 which stimulated FGFR2b-mediated keratinocyte proliferation. Postnatal deletion of FGFR2b in mice resulted in severe sebaceous gland atrophy. The importance of FGFR2b in sebaceous gland physiology is further supported by the mode of action of anti-acne agents which have been proposed to attenuate FGFR2b-signaling. Downregulation of FGFR2b-signaling by isotretinoin explains its therapeutic effect in acne. Downregulation of FGFR2b-signaling during the first trimester of pregnancy disturbs branched morphogenesis and explains retinoid embryotoxicity. Insulin-like growth factor-1 (IGF-1), the mediator of growth hormone during puberty, intracts with androgen-dependent FGFR2b-signaling and links androgen- and FGF-mediated signal transduction important in sebaceous gland homeostasis. The search for a follicular defect in the dermalepithelial regulation of growth factor-signaling in acne-prone skin appears to be a most promising approach to clarify the pathogenesis of acne.
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PMID:Role of FGFR2-signaling in the pathogenesis of acne. 2043 82

Eight cases of the acanthosis nigricans form of epidermal nevus have been described in literature. The present case is impressive and has an extensive segmental distribution. Although etiological factors, such as mutations in the FGFR3 gene, are becoming recognized, treatment options remain limited. We present a case of a 14-year-old male with multiple hyperpigmented, hyperkeratotic plaques on the upper body, axillae, and groin with a segmental distribution following Blaschko lines. Histopathological investigation showed aspects of both acanthosis nigricans and epidermal nevus. So far, screening has not revealed any internal abnormalities. As previous cases show a clear association with internal diseases, repetitive screening for internal diseases and syndromes is suggested in the case of the acanthosis nigricans form of epidermal nevus. Treatment of the condition remains a challenge.
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PMID:Extensive segmental acanthosis nigricans form of epidermal nevus. 2057 62

BRAF exon 15 mutations have been identified in a large proportion of malignant melanomas, melanoma metastases and melanocytic nevi. Mutated BRAF is one of the potential activators of the mitogen-activated protein kinase (MAPK) signaling pathway by phosphorylating ERK (extracellular signal-regulated kinase). We therefore analyzed the correlation of BRAF V600E and ERK-activation in 20 malignant melanomas and 21 subsequently evolved, paired metastases of the same donor by BRAF exon 15 DNA sequencing and phospho-specific immunohistochemistry for ERK. Phospho-ERK expression was present in 84% of primary melanomas and in all 19 metastases analyzed. In contrast, BRAF mutational status was concordant in only 12/20 pairs (60%) of the primary melanoma and metastasis of the same patient. Surprisingly, the BRAF mutation did not correlate with pERK expression. As even single tumors showed heterogeneous staining for pERK, we used laser-capture microdissection to study BRAF V600E status in pERK positive and pERK negative cells separately. Even on the single cell level ERK activation did not correlate with the BRAF mutation. Our results demonstrate that, in melanomas, activation of the MAPK pathway can occur through signaling pathways operating independently of BRAF T1799A.
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PMID:Activation of the mitogen-activated protein kinase pathway in malignant melanoma can occur independently of the BRAF T1799A mutation. 2060 66

Activating FGFR3 mutations have been identified in a variety of benign skin lesions (seborrheic keratosis, epidermal nevus, solar lentigo). However, the functional consequences of these mutations in the human epidermis are unknown. We therefore analyzed functional effects of the common R248C mutation in HaCaT keratinocytes. The cells were stably transduced with the R248C FGFR3 mutation or FGFR3-IIIb wildtype sequence using a retroviral system. The R248C mutant keratinocytes revealed significantly enhanced cell growth compared with wildtype cells after reaching confluence. Likewise, apoptosis and attachment to fibronectin were significantly reduced in mutant cells. In contrast, there was no difference regarding migration and oncogene-induced senescence. Gene expression analysis revealed only a few differentially expressed genes between mutant and wildtype HaCaT keratinocytes. ERK1/2 appear to be involved in the FGFR3-dependent signalling of R248C mutant keratinocytes. Our results indicate that an increased cell number at confluence along with reduced apoptosis may contribute to the growth of benign acanthotic tumors in the human epidermis.
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PMID:[R248C FGFR3 mutation. Effect on cell growth, apoptosis and attachment in HaCaT keratinocytes]. 2071 86

In the initial period after melanoma was recognised as a disease entity in the early 1800's, it was subclassified on the basis of its presumed origin (from a precursor naevus, from a melanocytic precursor lesion acquired during adult life or in previously blemish-fee skin). In 1967 the eminent American pathologist, Dr Wallace Clark, proposed a histogenetic classification for melanoma in which the disease was subdivided predominantly on the basis of histopathological features of the intra-epidermal component of the tumour adjacent to any dermal invasive component. The subtypes were superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM) and nodular melanoma (NM). Whilst additional entities, including acral lentiginous melanoma, mucosal melanoma, desmoplastic melanoma and naevoid melanoma have since been recognised, SSM, LMM and NM remain in the latest (2006) version of the WHO melanoma classification. Clark's histogenetic classification has been criticised because the criteria upon which it is based include clinical features (such as the site of the melanoma) and non-tumourous histopathological features (such as the character of the associated epidermis and the degree of solar elastosis) and also because of overlap in defining features, lack of an independent association with patient outcome and minimal relevance as a determinant of clinical management. However, such criticisms fail to acknowledge its importance in highlighting the myriad of clinical and histological guises of melanoma, which if not recognized by clinicians and pathologists will inevitably lead to a delay in diagnosis and a concomitant adverse clinical outcome. Recently, mutually exclusive oncogenic mutations in melanomas involving NRAS (15-20%), BRAF (50%), CKIT (2%), and GNAQ/GNA11 (50% of uveal melanomas) have been identified. This might herald the beginning of a new molecular classification of melanoma in which the biologically distinct subsets share a common oncogenic mechanism, behave clinically in a similar fashion and require similar clinical management. These discoveries are already being successfully exploited as therapeutic targets in clinical trials of metastatic melanoma patients with promising activity. Whilst there remains much to be discovered in this rapidly evolving field, there is already great optimism that more rational and effective therapies for melanoma patients will soon be widely available.
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PMID:Evolving concepts in melanoma classification and their relevance to multidisciplinary melanoma patient care. 2148 6


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