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

Early-onset melanoma under the age of 20 years is still a rare disease but has an increasing incidence. The aim of this study was to determine whether CDKN2A germline mutations are present in patients diagnosed with childhood/adolescent melanoma. From the Swedish Cancer Register we identified 60 patients with a diagnosis of cutaneous malignant melanoma before the age of 20 years. A medical history including information on self-reported melanoma heredity was obtained, a physical examination was performed by a dermatologist, and the histopathology slides were reviewed. A blood test was obtained for analysis of germline CDKN2A exon 1 and exon 2 mutations by DNA sequencing. We found only one germline CDKN2A mutation with functional significance, which was an exon 1 missense mutation resulting in a proline-to-leucine substitution in codon 48. This mutation was seen in a patient belonging to a previously reported kindred with hereditary melanoma where this particular germline CDKN2A mutation had been identified. Thus, in the large majority of cutaneous melanoma in childhood/adolescence, any underlying genetic alterations have yet to be identified.
Melanoma Res 2004 Aug
PMID:Germline CDKN2A mutations are rare in child and adolescent cutaneous melanoma. 1530 54

Melanoma progression is well defined in its clinical, histopathological and biological aspects, but the molecular mechanism involved and the genetic markers associated to metastatic dissemination are only beginning to be defined. The recent development of high-throughput technologies aimed at global molecular profiling of cancer is switching on the spotlight at previously unknown candidate genes involved in melanoma, such as WNT5A and BRAF. In fact, several tumor suppressors and oncogenes have been shown to be involved in melanoma pathogenesis, including CDKN2A, PTEN, TP53, RAS and MYC, though they have not been related to melanoma subtypes or validated as prognostic markers. Here, we have reviewed the published data relative to the major genes involved in melanoma pathogenesis, which may represent important markers for the identification of genetic profiles of melanoma subtypes.
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PMID:Genetic progression of metastatic melanoma. 1536 39

Although the presence of multiple cases of melanoma on the same side of a family is the best predictor of germline CDKN2A mutation, other features (i.e. early age at onset) may be useful to identify carriers. We analysed the records of 682 hospital-based Ligurian melanoma patients. Of these, 238 cases (34 familial, 14 non-familial multiple primary and 190 non-familial single primary melanomas) were consecutively enrolled for screening of the CDKN2A and CDK4 genes. Screening of the 34 familial patients revealed that nine were carriers of the CDKN2A G101W founder mutation. Of the 14 non-familial multiple primary melanoma patients, three carried the G101W founder mutation and one the P48T mutation. For the non-familial patients with a single melanoma, 17 of 190 carried germline CDKN2A mutations, with most (16/17) carrying the G101W Ligurian founder mutation and one a novel single base pair substitution, D74Y. The effect of mutation on age at diagnosis was significant (P=0.012) after correcting for melanoma type (familial or non-familial), number of primaries (single or multiple), gender and disease occurrence (incident or prevalent). Early age at onset may be a good predictor of CDKN2A mutation in Liguria, where the G101W founder mutation is prevalent among melanoma patients, independent of family history.
Melanoma Res 2004 Dec
PMID:Early onset may predict G101W CDKN2A founder mutation carrier status in Ligurian melanoma patients. 1557 13

Melanoma is the leading cause of death from skin tumors worldwide, with an annual increase in incidence over the past decade. The molecular mechanisms involved in melanoma pathogenesis are beginning to be unraveled. While a family history of melanoma and exposure to ultraviolet irradiation have been known for years as risk factors in melanoma development, the precise genes involved in inherited predisposition were defined only in the past decade. Germline mutations in two genes that play a pivotal role in controlling cell cycle and division--CDKN2A and cyclin-dependent kinase 4 (CDK4)--have been detected in autosomal, dominant, high penetrance familial melanoma cases. In addition to these two highly penetrant genes, germline mutations and polymorphisms in a few low penetrance genes have been reported in familial melanoma cases: melanocortin-1 receptor, epidermal growth factor, glutathione s-transferase M1, cytochrome p450 debrisoquine hydroxylase locus (CYP2D6) and vitamin D receptor.
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PMID:Genetics in melanoma. 1560 95

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.
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PMID:The genetics of susceptibility to cutaneous melanoma. 1588 16

Melanoma-associated germline mutations affecting the tumor suppressor and cyclin-dependent kinase (CDK) inhibitor, CDKN2A/p16INK4a, have been identified in over 100 melanoma-prone families worldwide. To predict the melanoma risk for carriers of specific mutations, mutant p16INK4a can be tested in biochemical and cellular assays. In most cases, p16INK4a mutations with predicted disease relation, due to segregation with melanoma, are functionally impaired in such assays. The N-terminal 24 base pair duplication of CDKN2A, however, encodes a p16INK4a variant previously shown to have wild-type function, despite segregating with melanoma in at least 5 melanoma families. To clarify whether the duplication mutation has a cell cycle regulatory defect or behaves like wild-type p16INK4a, we reanalyzed the cell cycle-inhibitory activity of this mutation. Stable cell clones of the p16-null WMM1175 melanoma cell line inducible for ectopic p16INK4a were used in this study. In these cells, p16INK4a expression can be controlled at physiologic levels. Our results show that in comparison to wild-type p16INK4a, the duplication mutant induced weaker S-phase inhibition and cells expressing this mutant form of p16INK4a retained colony formation ability. We also show that the cell cycle-regulatory defect of the p16INK4a duplication mutant was associated with decreased inhibition of pRb phosphorylation even though it retained significant binding to CDK4.
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PMID:The melanoma-associated 24 base pair duplication in p16INK4a is functionally impaired. 1594

Cutaneous melanoma remains a management challenge. Melanoma is the leading cause of death from skin tumors worldwide. Melanoma progression is well defined in its clinical, histopathological and biological aspects, but the molecular mechanism involved and the genetic markers associated to metastatic dissemination are only beginning to be defined. The recent development of high-throughput technologies aimed at global molecular profiling of cancer is switching on the spotlight at previously unknown candidate genes involved in melanoma. Among those genes, BRAF is one of the most supposed to be of interest and targeted therapies are ongoing in clinical trials. In familial melanoma, germline mutations in two genes, CDKN2A and CDK4, that play a pivotal role in controlling cell cycle and division. It is hope that this better understanding of the biologic features of melanoma and the mechanisms underlying tumor-induced immunosuppression will lead to efficaceous targeted therapy.
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PMID:[Genotypic hypervariability of melanoma: a therapeutic challenge]. 1645 59

Cutaneous malignant melanoma remains the leading cause of skin cancer death in industrialized countries. Melanoma progression is well defined in its clinical and histopathological aspects (Breslow's index, tumour size, ulceration, or vascular invasion), which also give hints to prognosis of the patient. Use of molecular markers should therefore give additional information which cannot be determined by routine histopathology. Markers showing only a correlation to Clark level or tumour size are not useful. Several molecules influencing invasiveness and metastatic dissemination of melanoma have been identified. Expression of these molecules has been studied in primary melanoma and correlated with prognosis. Moreover, several tumour suppressors and oncogenes have been shown to be involved in melanoma pathogenesis, including CDKN2A, PTEN, TP53, RAS and MYC, but have not been related to melanoma subtypes or validated as prognostic markers. In the past, in melanoma, an increase in the number of positive tumour cells for Ki67 (detected by Mib1), cyclin A, cyclin D, MMP-2, integrins beta1 and beta3 or osteonectin were considered as factors of poor prognosis as well as the decrease in p16, p27, and Melan A. However, only a small subset of these proteins has a prognostic value independent of tumour thickness. The recent development of high-throughput technologies analyzing global molecular profiles of cancer is bringing up previously unknown candidate genes involved in melanoma, such as Wnt-5A and B-raf. Here, recently published data related to new genes involved in melanoma pathogenesis, which may represent important biomarkers for the identification of genetic profiles or indication of progression of melanoma, are reviewed.
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PMID:Novel biomarkers in malignant melanoma. 1648 Jun 99

We studied differential global gene expression in four melanoma cell lines with three cell lines without homozygous deletion of the CDKN2A locus using HG-U133A microarrays with 22 277 transcripts. None of the cell lines carried mutations in the B-RAF and N-RAS genes. Data analysis using stringent criteria showed specific upregulation of 70 genes and downregulation of 86 genes in cell lines with homozygous deletion of the CDKN2A gene. A comparison with previous expression data showed overlapping of upregulation and downregulation of seven and 23 genes, respectively, in melanoma cell lines with homozygous deletion of the CDKN2A locus or mutations in the B-RAF and N-RAS genes. Microarray data for eight selected genes were validated with an extended number of cell lines using quantitative real-time polymerase chain reaction. The upregulated genes in cell lines with the deletion besides others included MAGE A2 [fold change 128, 95% confidence interval (CI) 82.8-172.2; t-test P=0.004], MAGE A6 (fold change 623, 95% CI 473.4-772.1; t-test P=0.001), MAGE A12 (fold change 90, 95% CI 65.1-115.5; t-test P=0.001) and dopachrome tautomerase (fold change 42, 95% CI 32.5-51.8; t-test P=0.001). Downregulated genes included interleukin 18 (fold change 489, 95% CI 146.4-831.2; t-test P=0.04), ID2 (fold change 3, 95% CI 2.2-4.9; t-test P=0.001), KLF4 (fold change 9, 95% CI 4.3-14.7; P=0.01) and CD24 antigen (fold change 1308, 95% CI 766.0-1850.8; t-test P=0.01). The upregulated genes common to cell lines with homozygous deletion of the CDKN2A gene and mutations in B-RAF and N-RAS gene included those that are involved in RAS/RAF/MEK/ERK pathways. Our results highlight effects of homozygous deletion of the CDKN2A locus on global gene expression.
Melanoma Res 2006 Aug
PMID:Differences in global gene expression in melanoma cell lines with and without homozygous deletion of the CDKN2A locus genes. 1684 25

Germline mutations of the CDKN2A and CDK4 genes explain a significant proportion of familial melanoma. To date, there have been few published estimations of the prevalence of such mutations in sporadic melanoma patients. In this study, we investigated CDKN2A and CDK4 exon 2 for germline mutations in 125 consecutive cutaneous malignant melanoma patients recruited through the Latvian Oncological Center, using amplicon melting analysis and sequencing. No disease-related CDKN2A germline mutations were identified in any of the melanoma patients analysed but the previously described CDK4 mutation, Arg24His, was found in one patient with a family history of melanoma. CDKN2A polymorphisms were studied as putative low penetrance susceptibility genes. The proportion of cases with polymorphisms in this Latvian melanoma population was Ala148Thr (c.442G>A) (6%), 500 C/G (c.*29C>G) (18%), and 540 C/T (c.*69C>T) (20%); however, only the frequency of the Ala148Thr polymorphism was higher in melanoma patients than in 203 controls (6 versus 1%, P=0.03). Ala148Thr has also been reported in association with melanoma in a Polish series but not in an English series. We therefore examined the Ala148Thr carrier's haplotype in 10 Latvian and 39 Polish samples. No significant difference was seen between these populations and the predominant haplotype observed in English samples, giving no indication that the discrepancy could be explained by population differences in linkage disequilibrium. In summary, our results show that germline mutations at the CDKN2A locus are rare in sporadic melanoma in Latvia. The study does, however, provide some additional evidence for a role for the CDKN2A polymorphism Ala148Thr as a low penetrance susceptibility gene. The detected CDK4 exon 2 mutation was found in only the seventh family identified worldwide with a germline CDK4 mutation.
Melanoma Res 2007 Jun
PMID:CDKN2A and CDK4 variants in Latvian melanoma patients: analysis of a clinic-based population. 1750 64


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