Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C1522102 (Melanoma)
 7,698 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Melanoma is the most aggressive of the skin cancers and its prognosis is often poor. The only known environmental risk factor for this tumour is ultraviolet light exposure. This fact together with the existence of melanoma-prone families has prompted investigation of genetic risk factors that may be involved in melanoma development. Inactivation of the INK4a/p16 gene is known to play a role in familial cases. Data on genes or loci involved in sporadic melanoma are less definitive and require more detailed research. In addition to the INK4a locus, other genes involved in melanoma development are discussed here, in particular those genes that participate in the same functional pathway, such as CDK4 and Rb, and p53, which is regulated by the alternative product of INK4a. Evidence showing the possible location of melanoma susceptibility genes on chromosomes 1p, 6, 10q and 11q is analysed along with data showing N-ras, betacatenin, c-myc and MC1R involvement. Melanoma is a well-characterized disease in terms of its progression stages; therefore obtaining precise genetic information is crucial in the development of a stepwise model of melanoma pathogenesis.
Melanoma Res 1999 Oct
PMID:Genes involved in melanoma: an overview of INK4a and other loci. 1059 8

Melanoma incidence has risen in many Caucasians populations over the last 20 years and research on the potential environmental and genetic risk factors has led to some interesting new findings but also to many more questions. The relationship between melanoma and ultraviolet radiation is complex and this area of research is controversial especially regarding the use of sunbeds and sunscreens. In terms of genetic factors, the discovery of two genes CDKN2A and CDK4 has been a great advance with more understanding of melanocyte biology in relation to defects in senescence. For phenotypic risk factors such as fair skin and high numbers of naevi, the role of genetic factors is clearly evident but these traits are complex and the discovery of genes involved in skin pigmentation and naevi formation is not an easy task. Research on the MC1R gene has not only shown the importance of this gene in hair and skin pigmentation but also in senescence and immunity. Functional studies involving CDKN2A and MC1R are leading to important new findings. There is also some hope regarding the use of micro-arrays in helping to dissect many genetic events in melanoma. The collection of large datasets including family, twin and case-control studies as well as tumour banks with collaborations between countries will hopefully lead to more discoveries. For the primary and secondary prevention of this tumour, efforts need to be sustained in public health campaigns on sun exposure and the recognition of individuals at high risk.
 ...
PMID:Genetic epidemiology of melanoma. 1282 35

The most common genetic determinants of skin cancer are the genes that control skin color so that the genes expressed as black skin are protective. Within the white population variants at the MC1R locus are shown to increase susceptibility, and recent evidence suggests that polymorphisms in the OCA2 gene interact to modify risk. Other as-yet-unidentified pigment genes may also play a role in susceptibility to melanoma. Thus MC1R variants are the most common low-penetrance melanoma-susceptibility genes so far identified. Other putative low-penetrance susceptibility genes have been explored using candidate gene approaches. Good candidates such as the DNA repair gene XRCC3 and polymorphisms of EGF have been studied but excluded. Other candidates such as BRAF polymorphisms and variants at the CDKN2A locus remain to be fully investigated. More progress has been made in identifying high-penetrance genes, however. The most common (and probably the most penetrant) susceptibility locus is the CDKN2A locus coding for two tumor suppressor proteins, p16 and p14ARF. Mutations at this locus that impact p16, p14ARF or both proteins all increase susceptibility to melanoma. Families inheriting such mutants are at increased risk of cutaneous melanoma, and the penetrance is increased by residence in sunny climates and co-inheritance of MC1R variants. Some families also appear to be at increased risk of pancreatic cancer, but the determinants of susceptibility to pancreatic cancer are not yet understood. Very rare families have germline mutations in the CDK4 gene which impact on the p16 binding site. There are other high-penetrance susceptibility genes, however, which remain undiscovered. There is evidence of one at 1p22. The Melanoma Genetics Consortium (www.genomel.org) continues to explore this and the genetic epidemiology of the CDKN2A locus.
 ...
PMID:The genetics of susceptibility to cutaneous melanoma. 1588 16

Spontaneous or therapy-induced depigmentation in patients with melanoma has long been considered a favourable prognostic indicator. In this report, we isolated T cells infiltrating the depigmented skin of an HLA-A2+/DR4+ patient with melanoma, and detected a very high frequency of CD8+ T cells specific for melanocortin receptor 1 (MC1R), a hormone receptor involved in cutaneous pigmentation. In particular, tissue-infiltrating CD8+ T cells dominantly recognized the novel MC1R52-60 peptide epitope in an HLA-A2-restricted manner, and peptide-reactive CD8+ T cells were also detected in freshly isolated peripheral blood from this patient. Although type 1 CD4+ T-cell responses against MC1R were not detected in fresh tissue isolates, short-term in-vitro stimulation of peripheral blood lymphocytes resulted in the rapid expansion of CD4+ T cells reactive against novel HLA-DR4-presented epitopes derived from the MC1R protein (i.e. MC1R82-95, MC1R105-118 and MC1R149-161). MC1R peptide-specific CD8+ T-cell clones isolated from the depigmented skin of this patient were characterized by comparatively low functional avidity for specific major histocompatibility complex-peptide complexes and were poorly lytic; however, these effector cells were capable of secreting both interferon-gamma and granzyme B against relevant target cells in vitro, and may have played an important role in the induction of leucoderma in situ in this patient.
Melanoma Res 2006 Apr
PMID:Accumulation of low-avidity anti-melanocortin receptor 1 (anti-MC1R) CD8+ T cells in the lesional skin of a patient with melanoma-related depigmentation. 1656 72

MC1R sequence variants are associated with malignant melanoma risk, and most commonly are missense mutations. Few (n=9) truncating mutations have been described in this gene as predisposing to malignant melanoma. In this study, three Jewish individuals were found to harbor an identical truncating MC1R mutation--Y152X: an Ashkenazi patient with two malignant melanomas, a non-Ashkenazi malignant melanoma patient with familial malignant melanoma and her asymptomatic mother. Both malignant melanoma patients carried additional, seemingly pathogenic MC1R variants. Haplotype analysis revealed that all three mutation carriers shared the same haplotype. This sequence variant was previously described in ethnically diverse, non-Jewish individuals and in all likelihood represents an error-prone domain that, in conjunction with other genetic and environmental factors, increases malignant melanoma risk.
Melanoma Res 2007 Apr
PMID:The Y152X MC1R gene mutation: occurrence in ethnically diverse Jewish malignant melanoma patients. 1749 85

A significantly increased susceptibility to melanoma may manifest as a family history of melanoma (plus or minus pancreatic cancer), the development of multiple primary tumors, or melanoma in the context of numerous and clinically atypical moles (the atypical mole syndrome). In families, increased susceptibility may occur as a result of the inheritance of mutations at the CDKN2A locus or in the CDK4 gene. We describe what is known about these genes and discuss the implications for genetic counseling and gene testing. Lower levels of risk are associated with genetically determined pigmentary variation within populations. This variation is attributable to inheritance of variants in the MC1R gene and putatively other genes such as OCA2, which is discussed. Melanoma is causally related to sun exposure in the majority of patients, although the patterns of sun exposure, which are most important, remain controversial. The role of risk estimation for individuals in giving advice about sun exposure is considered.
 ...
PMID:Genetics: what advice for patients who present with a family history of melanoma? 1808 68

We evaluated the contribution of germline CDKN2A mutations and MC1R variants to the development of melanoma in a hospital-based study of single (SPM, n = 398) and multiple primary melanoma (MPM, n = 95). The overall frequency of CDKN2A mutations was 15.2%, and four-fold higher in MPM than in SPM cases (OR = 4.27; 95% CI 2.43-7.53). The likelihood of identifying a CDKN2A mutation increased with family history of melanoma and younger age at diagnosis in MPM cases. Compared to SPM patients, the risk of harboring a CDKN2A mutation rose as the number of primary melanomas increased and was not influenced by family history. The G101W and E27X founder mutations were the most common. Several other mutations (W15X, Q50X, R58X, A68L, A127P and H142R) were detected for the first time in Italian patients. One novel mutation, T77A, was identified. Several non-coding variants with unknown functional significance were also found (5'UTR -25C > T, -21C > T, -67G > C, IVS1 +37G > C); the novel 5'UTR -21C > T variant was not detected in controls. The CDKN2A A148T polymorphism was more frequent in MPM patients than in the control population (15.7% versus 6.6%). Compared to the SPM patients, MPM cases had a 2-fold increased probability of being MC1R variant carriers and a higher probability of carrying two or more variants. No specific association was observed between the type of variant and the number of melanomas, suggesting that the number rather than the type of MC1R variant increases the risk of MPM. We observed no interaction between CDKN2A status and the presence of MC1R variants. The high frequency of CDKN2A mutations in our MPM cases, independent of their family history, is of relevance to genetic counseling and testing in our population.
Pigment Cell Melanoma Res 2008 Dec
PMID:CDKN2A mutations and MC1R variants in Italian patients with single or multiple primary melanoma. 1898 35

The genetic background of cutaneous malignant melanoma (CMM) includes both germ line aberrations in high-penetrance genes, like CDKN2A, and allelic variation in low-penetrance genes like the melanocortin-1 receptor gene, MC1R. Red-hair colour associated MC1R alleles (RHC) have been associated with red hair, fair skin and risk of CMM. We investigated MC1R and CDKN2A variation in relation to phenotype, clinical factors and CMM risk in the Swedish population. The study cohort consisted of sporadic primary melanoma patients, familial melanoma patients and a control group. An allele-dose dependent increase in melanoma risk for carriers of variant MC1R alleles (after adjusting for phenotype), with an elevated risk among familial CMM patients, was observed. This elevated risk was found to be significantly associated with an increased frequency of dysplastic nevi (DN) among familial patients compared to sporadic patients. MC1R variation was found to be less frequent among acral lentiginous melanomas (ALM) and dependent on tumour localisation. No association was found between CDKN2A gene variants and general melanoma risk. Two new variants in the POMC gene were identified in red haired individuals without RHC alleles.
Pigment Cell Melanoma Res 2009 Apr
PMID:MC1R variation and melanoma risk in the Swedish population in relation to clinical and pathological parameters. 1907 44

We previously reported that topical application of forskolin to the skin of fair-skinned MC1R-defective mice with epidermal melanocytes resulted in accumulation of eumelanin in the epidermis and was highly protective against UV-mediated cutaneous injury. In this report, we describe the long-term effects of chronic topical forskolin treatment in this animal model. Forskolin-induced eumelanin production persisted through 3 months of daily applications, and forskolin-induced eumelanin remained protective against UV damage as assessed by minimal erythematous dose (MED). No obvious toxic changes were noted in the skin or overall health of animals exposed to prolonged forskolin therapy. Body weights were maintained throughout the course of topical forskolin application. Topical application of forskolin was associated with an increase in the number of melanocytes in the epidermis and thickening of the epidermis due, at least in part, to an accumulation of nucleated keratinocytes. Together, these data suggest in this animal model, short-term topical regular application of forskolin promotes eumelanin induction and that over time, topical forskolin treatment is associated with persistent melanization, epidermal cell accumulation, and skin thickening.
Pigment Cell Melanoma Res 2009 Apr
PMID:Prolonged treatment of fair-skinned mice with topical forskolin causes persistent tanning and UV protection. 1908 31

Amelanotic melanoma (AM) is a rare subtype of melanoma with little or no clinically visible pigment; it is more difficult to diagnose than pigmented melanoma (PM), and has a worse prognosis. In the attempt to find a genetic explanation for the distinction between AM and PM, we conducted a case-case study, matching AM and PM patients, and testing them for germline mutations in high- (p16INK4A, p14ARF, CDK4) and low-penetrance (MC1R) melanoma susceptibility genes. Similar CDKN2A mutations were found in both sets of melanomas. A p14ARF splice germline mutation was detected for the first time in an Italian family with AM. This rare mutation, which has been described only once previously, may be involved in predisposition to the amelanotic phenotype in combination with germline MC1R variants and coordinate somatic expression of pigmentation genes and their regulators.
Melanoma Res 2009 Jun
PMID:CDKN2A and MC1R analysis in amelanotic and pigmented melanoma. 1933 2


1 2 3 4 Next >>