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)

The P48T germ line mutation of p16 was detected in a Hungarian multiple primary melanoma patient (deceased at the age of 39) with no affected family members. Genetic analysis of the patient and his family revealed that the patient was homozygous for the mutation, whereas his parents (father currently aged 69 and mother 63), who are free from any malignancies and atypical moles, are both heterozygous for the mutation. Our data suggest that the P48T mutation of p16 is a strong melanoma-predisposing factor, but the fact that the heterozygous mutant parents have not yet exhibited melanoma or atypical moles indicates that the penetrance of this allele might depend on modifying factors. The rare P48T germ line mutation of p16 has been reported previously in only four independent studies, all in patients with Italian ancestry. Here, we first report the inheritance of the rare P48T mutation of CDKN2A in a Hungarian family with a homozygous multiple primary melanoma member and unaffected heterozygous family members. The question of whether the mutation detected in Hungary is the result of an independent event, or migration of the founder mutation occurred at some time in the past, necessitates further investigations.
Melanoma Res 2007 Aug
PMID:First detection of the melanoma-predisposing proline-48-threonine mutation of p16 in Hungarians: was there a common founder either in Italy or in Hungary? 1762 56

Melanoma is the most dangerous of all common skin cancers, due to its propensity to metastasize. Therefore, identification of at-risk populations may allow early detection of disease at a curable stage. In Europe and North America, between 8-14% of melanoma patients have a family history of the disease, and a subset of these individuals possess germline mutations in the CDKN2A gene, which encodes the p16(INK4A) and p14(ARF) tumor suppressors. We identified 30 patients (29 families) from Southern Brazil, who had a family history of melanoma and/or pancreatic cancer; or a personal history of multiple primary melanoma. We screened this cohort for mutations in the CDKN2A and CDK4 genes, and detected two functional mutations: a G-34T transversion in 5'untranslated region; and a M53I alteration encoded in exon 2. Both mutants have been previously associated with melanoma and demonstrate founder effects. We conclude that germline mutations of CDKN2A occur in the Brazilian population, and that these mutations likely originated in Europe.
 ...
PMID:Clinical and molecular characterization of patients at risk for hereditary melanoma in southern Brazil. 1771 69

We have investigated the frequency and spectrum of CDKN2A/CDK4 mutations in 23 cutaneous melanoma families from Central Italy (Tuscany). Three distinct mutations were identified in five families. One mutation, p.G23S, was present in three families. Several lines of evidence indicate that p.G23S is a pathogenic mutation: it is located in the functionally important first ankyrinic domain of p16, it was not detected in a sample of 100 control individuals, and it was present in all tested affected individuals from the three families. Haplotype analysis showed a common ancestral origin of the p.G23S mutation. Our data show that the p.G23S mutation is an important cause of hereditary melanoma in Tuscany.
Melanoma Res 2007 Dec
PMID:The p.G23S CDKN2A founder mutation in high-risk melanoma families from Central Italy. 1799 22

A complex interaction of genetic, host, and environmental factors results in cutaneous malignant melanoma, the fifth most common cancer among men and the sixth among women in the United States. Mortality rates for cutaneous malignant melanoma depend on stage at diagnosis; thus, efforts are aimed at early detection and identification of risk factors for melanoma to distinguish those individuals requiring close surveillance. Melanoma susceptibility genes CDKN2A and CDK4 play a role in the development of melanoma, especially among some familial melanoma kindreds. The functions of CDKN2A and CDK4 in melanoma development, however, are currently incompletely understood. Therefore, at this time, predictive genetic testing for CDKN2A mutations outside of defined research protocols is not recommended because of the low likelihood of detecting mutations even in high-risk groups, the present inadequacy of interpreting a test result due to variations in penetrance and unclear associations with other cancers, and the minimal influence knowledge of mutation status currently has on medical management. Oncology nurses have an important role in identifying individuals at high risk for melanoma regardless of CDKN2A mutation status, encouraging enrollment in skin surveillance programs, and providing patient education regarding sun protection, prevention and early detection of melanoma.
 ...
PMID:Genetic testing for melanoma predisposition: current challenges. 1802 17

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

Rapid advances have been made in our knowledge of the commonest genetic and epigenetic alterations found in human sporadic melanomas. Valuable recent contributions came from analyses of gene copy number by comparative genome hybridization, and from large-scale gene expression profiling. All of the commonest affected genes encode regulatory components. Loci with established importance in melanoma, like CDKN2A, BRAF and PTEN, have been joined by some less familiar genes including transcription factor sequences TBX2 and STK11 (LKB). This knowledge is reviewed in relation to the cellular signaling pathways affected by these molecules, their biological outcomes, and the implications as to what changes are required overall to generate a melanoma. The data support a model in which genesis of melanoma requires changes that (1) initiate clonal expansion, (2) overcome cell senescence, and (3) reduce apoptosis.
Pigment Cell Melanoma Res 2008 Feb
PMID:How to make a melanoma: what do we know of the primary clonal events? 1835 41

CDKN2A is the major melanoma susceptibility gene so far identified, but only 40% of three or more case families have identified mutations. A comparison of mutation detection rates was carried out by "blind" exchange of samples across GenoMEL, the Melanoma Genetics Consortium, to establish the false negative detection rates. Denaturing high performance liquid chromatography (DHPLC) screening results from 451 samples were compared to screening data from nine research groups in which the initial mutation screen had been done predominantly by sequencing. Three samples with mutations identified at the local centres were not detected by the DHPLC screen. No additional mutations were detected by DHPLC. Mutation detection across groups within GenoMEL is carried out to a consistently high standard. The relatively low rate of CDKN2A mutation detection is not due to failure to detect mutations and implies the existence of other high penetrance melanoma susceptibility genes.
 ...
PMID:A comparison of CDKN2A mutation detection within the Melanoma Genetics Consortium (GenoMEL). 1839 81

The inactivation of tumor-related genes through the aberrant methylation of promoter CpG islands is thought to contribute to tumor initiation and progression. We therefore investigated promoter methylation events involved in cutaneous melanoma by screening 30 genes of interest for evidence of promoter hypermethylation, examining 20 melanoma cell lines and 40 freshly procured melanoma samples. Utilizing quantitative methylation-specific PCR, we identified five genes (SOCS1, SOCS2, RAR-beta 2, TNFSF10C, and TNFSF10D) with hypermethylation frequencies ranging from 50% to 80% in melanoma cell lines as well as freshly procured tissue samples. Eighteen genes (LOX, RASSF1A, WFDC1, TM, APC, TFPI2, TNFSF10A, CDKN2A, MGMT, TIMP3, ASC, TPM1, IRF8, CIITA-PIV, CDH1, SYK, HOXB13, and DAPK1) were methylated at lower frequencies (2-30%). Two genes (CDKN1B and PTEN), previously reported as methylated in melanoma, and five other genes (RECK, IRF7, PAWR, TNFSF10B, and Rb) were not methylated in the samples screened here. Daughter melanoma cell lines showed identical methylation patterns when compared with original samples from which they were derived, as did synchronous metastatic lesions from the same patient. We identified four genes (TNFSF10C, TNFSF10D, LOX, and TPM1) that have never before been identified as hypermethylated in melanoma, with an overall methylation frequency of 60, 80, 50, and 10%, respectively, hypothesizing that these genes may play an important role in melanoma progression.
Pigment Cell Melanoma Res 2008 Oct
PMID:Identification of novel epigenetically modified genes in human melanoma via promoter methylation gene profiling. 1862 28

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

Predisposition to familial cutaneous malignant melanoma has been associated with mutations in the CDKN2A and CDK4 genes. However, only a small subgroup of melanoma pedigrees harbour CDKN2A or CDK4 germline mutations. It is possible that other types of CDKN2A rearrangements, not detectable by routine PCR-based approaches, are involved in a fraction of melanoma cases negative for point sequence changes. In order to gain insights on the possible role of CDKN2A large deletions or duplications in melanoma susceptibility in the Italian population, we screened a series of 124 cutaneous malignant melanoma families referred to five national medical/cancer genetics centres. All probands were negative for point mutations in CDKN2A and CDK4. All samples were tested by MLPA (multiplex ligation-dependent probe amplification), and the results were confirmed by real-time quantitative PCR in a subset of 53 cases. No genomic rearrangements were detected in this series, one of the largest so far investigated. These data suggest that large deletions/duplications in the CDKN2A locus are infrequently involved in the development of familial melanoma in the Italian population. Based on these results, routine search for these rearrangements in CDKN2A- and CDK4-mutation negative melanoma families is not warranted, although it would be reasonable to pursue it in selected cases with very strong family history and/or showing linkage to 9p21.
Melanoma Res 2008 Dec
PMID:Genomic rearrangements of the CDKN2A locus are infrequent in Italian malignant melanoma families without evidence of CDKN2A/CDK4 point mutations. 1901 13


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>