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Query: UMLS:C0027960 (mole)
 21,279 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A large number of nevi (LNN) is a high risk phenotypic trait for developing cutaneous malignant melanoma (CMM). In this study, the breakpoints of a t(9;12)(p21;q13) balanced chromosome translocation were finely mapped in a family with LNN and CMM. Molecular characterization of the 9p21 breakpoint identified a novel gene C9orf14 expressed in melanocytes disrupted by the translocation. Integrative analysis of functional genomics data was applied to determine the role of C9orf14 in CMM development. An analysis of genome-wide DNA copy number alterations in melanoma tumors revealed the loss of the C9orf14 locus, located proximal to CDKN2A, in approximately one-fourth of tumors. Analysis of gene expression data in cancer cell lines and melanoma tumors suggests a loss of C9orf14 expression in melanoma tumorigenesis. Taken together, our results indicate that C9orf14 is a candidate tumor-suppressor for nevus development and late stage melanoma at 9p21, a region frequently deleted in different types of human cancers.
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PMID:Molecular characterization of a t(9;12)(p21;q13) balanced chromosome translocation in combination with integrative genomics analysis identifies C9orf14 as a candidate tumor-suppressor. 1709 75

Oncologists who are aware of the progress in hereditary cancer syndrome diagnosis, and, in particular, of how this effort may be effectively facilitated through a comprehensive family history in concert with molecular genetic studies, are in the envious position of designing highly targeted screening and management programs for the membership of these cancer-prone families. The Lynch syndrome is discussed as a clinical model wherein the presence of mismatch repair mutations provides a high level of diagnostic certainty for the initiation of targeted cancer screening and management. The familial atypical multiple mole melanoma-pancreatic cancer (FAMMM-PC) syndrome, on the other hand, provides another model with cancer-control potential. Given its phenotypic features of multiple atypical nevi, high total body mole count and cutaneous malignant melanoma, coupled with the integral association of PC in a subset of FAMMM kindreds with the CDKN2A germline mutation, this may result in a perhaps lower level of diagnostic certainty when compared with the Lynch syndrome. This knowledge may impact upon progress in the earlier diagnosis of melanoma and provide an impetus for creative diagnostic methods in PC, a disease that, at this time, demonstrates a mortality rate virtually identical to its incidence rate.
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PMID:Hereditary cancer syndrome diagnosis: molecular genetic clues and cancer control. 1738 17

The G101W founder mutation is the most common CDKN2A mutation in Italy, Spain, and France. As the background of modifying genes, environmental exposures, and sun behavior vary across countries, studying G101W carriers from distinct countries offers a unique opportunity to evaluate possible modifying factors in melanoma development. We evaluated 76 G101W cases and 59 carrier controls from France, Italy, Spain, and the United States. Hair color and dysplastic nevi distributions differed significantly in cases and controls across the 4 study groups. Cases also varied significantly for eye color, freckling, and nevi. The distribution of MC1R variants in cases differed significantly across study groups because 12% of Italian melanoma patients had > or =2 MC1R variants vs. >50% for the other case groups. Several MC1R covariates showed significant associations with melanoma risk in all groups combined and in the American, French, and Spanish samples; no significant findings were observed in the Italian sample. In multiple-case families, the number and type of MC1R variants varied significantly between multiple-primary-melanoma and single-primary-melanoma patients from the 4 groups; there was also a significant decrease in median age at melanoma diagnosis as the number or type of MC1R variants increased. The variation in the effects of the cutaneous phenotypic and MC1R factors across the study sample suggests that these factors differentially contribute to development of melanoma even on a common genetic background of a germline CDKN2A mutation. Differences in melanoma risk across geographic regions justify the need for individual studies in each country before counseling should be considered.
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PMID:Cutaneous phenotype and MC1R variants as modifying factors for the development of melanoma in CDKN2A G101W mutation carriers from 4 countries. 1739 31

Melanocytic lesions, including Spitz nevi (SN), common benign nevi (CBN) and cutaneous metastatic melanoma (CMM), were analyzed for activating mutations in NRAS, HRAS and BRAF oncogenes, which induce cellular proliferation via the MAP kinase pathway. One of 22 (4.5%) SN tested showed an HRAS G61L mutation. Another lesion, a 'halo' SN, showed a BRAF V600E (T1796A) mutation. BRAF V600E mutations were found in two thirds (20/31) of CBN, while a further 19% (6/31) showed NRAS codon 61 mutations. One third of CMM (10/30) had various BRAF mutations of codon 600, and a further 6% (2/31) showed NRAS codon 61 mutations. Seventeen SN tested for loss of heterozygosity (LOH) at 9p and 10q regions, known to be frequently deleted in melanoma, showed LOH at the 9p loci D9S942 and IFNA. A further lesion was found with low-level microsatellite instability at one locus, D10S214. The low rate of RAS-RAF mutations (2/22, 9.1%) observed in SN suggests that these lesions harbor as yet undetected activating mutations in other components of the RAS-RAF-MEK-ERK-MAPK pathway. Germline DNA from members of 111 multiple-case melanoma families, representing a range of known (CDKN2A) and unknown predisposing gene defects, was analyzed for germline BRAF mutations, but none was found.
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PMID:Low prevalence of RAS-RAF-activating mutations in Spitz melanocytic nevi compared with other melanocytic lesions. 1751 71

We studied gene expression in 18 melanocytic nevi with and four nevi without the V600E mutation in the BRAF gene using HG-U133A 2.0 microarray with 22,277 transcripts. Data analysis revealed 92 genes up-regulated and 105 genes down-regulated in nevi with the mutation compared to nevi without mutation. Pathway analysis showed that differentially regulated genes mapped to 10 genetic networks. The major network included genes involved in cell death, cell cycle, and cellular growth and proliferation. Up-regulated genes in nevi with the mutation included CDKN2A, CDKN1C, and MITF; whereas down-regulated genes included those involved in apoptotic and other pathways. Principal component analysis identified 22 probe sets (20 genes) that caused separate segregation of nevi with and without mutations. In conclusion, our data showed differences in gene expression between nevi with and without the V600E BRAF mutation. Moreover, nevi with mutations showed over-expression of genes involved in melanocytic senescence and cell cycle inhibition.
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PMID:Differential gene expression in melanocytic nevi with the V600E BRAF mutation. 1769 95

Hereditary cancer syndromes provide excellent models for molecular genetic studies that may aid significantly in case detection, surveillance, and management. Ultimately, molecularly based designer pharmaceuticals may emerge from this research, such as the case of trastuzumab (Herceptin) in HER-2/neu positive breast cancer, and imatinib (Gleevec) in chronic myelocytic leukemia and gastrointestinal stromal tumors. Importantly, these molecular findings may fuel significant clues to cancer control. This background is mentioned since surveillance and management of pancreatic cancer, a major concern of this manuscript, has been uniformly unsuccessful as evidenced by the close correspondence between its incidence and its mortality. Yet knowledge about its genetic and molecular pathology will hopefully ameliorate this vexing problem. One molecular genetic clue is the recently identified palladin mutation in two pancreatic cancer prone families. However, caution must be used toward the palladin mutation, as several recent publications have questioned its significance as a pancreatic cancer causing mutation. We provide a concise description of pancreatic cancer in concert with malignant melanoma in the familial atypical multiple mole melanoma (FAMMM) syndrome as a potential preventive model. This knowledge should help clinicians and basic scientists seize on the opportunity to develop more sensitive and specific screening and management programs in this disease; while a relatively small subset of pancreatic cancer may be readily identifiable through its FAMMM phenotype, coupled with its CDKN2A mutation, this hereditary disorder, given a keen knowledge of its natural history and molecular genetics, may prove to be an effective clinical preventive model.
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PMID:Pancreatic cancer and the FAMMM syndrome. 1799 82

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.
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PMID:Genetics: what advice for patients who present with a family history of melanoma? 1808 68

In most Dutch melanoma families, a founder deletion in the melanoma susceptibility gene CDKN2A (which encodes p16) is present. This founder deletion (p16-Leiden) accounts for a significant proportion of the increased melanoma risk. However, it does not account for the Atypical Nevus (AN) phenotype that segregates in both p16-Leiden carriers and non-carriers. The AN-affected p16-Leiden family members are therefore a unique valuable resource for unraveling the genetic etiology of the AN phenotype, which is considered both a risk factor and a precursor lesion for melanoma. In this study, we performed a genome-wide scan for linkage in four p16-Leiden melanoma pedigrees, classifying family members with five or more AN as affected. The strongest evidence for an atypical nevus susceptibility gene was mapped to chromosome band 7q21.3 (two-point LOD score=2.751), a region containing candidate gene CDK6.
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PMID:Genome-wide linkage scan for atypical nevi in p16-Leiden melanoma families. 1839 32

Recent studies have indicated an increasing incidence of melanoma worldwide. Although UV signature mutations are found rarely in melanoma cells, there is some evidence that intense intermittent exposure to sunlight can induce melanocyte tumorigenesis, and this is also observed after UV irradiation in some animals. The purpose of this paper is to review some of the most important mechanisms involved in the pathogenesis of this tumor. Genetic studies showed the familiar melanoma is linked to the mutation or deletion of the suppressor gene CDKN2A, and perhaps to CDK4. Studies showed that BRAF mutation is frequent in primary and metastatic melanoma cells but also in naevocytic nevi. This mutation activates the RAF/MEK pathway. Exposure to UV radiation induces immunosuppression. Recent investigations showed that chemokines, angiogenesis, metalloproteinases can play a role in the mechanism of metastasis. In spite of these advances the initiating events are still not completely understood. In conclusion, the pathogenesis of melanoma is very complex because numerous genetic and epigenetic factors are implicated in its development and progression, but some of the showed mechanisms can be targets for new therapies.
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PMID:Molecular and genetic mechanisms in melanoma. 1913 18

Some cases of pancreatic cancer (PC) are described to cluster within families. With the exception of PALLD gene mutations, which explain only a very modest fraction of familial cases, the genetic basis of familial PC is still obscure. Here the literature was reviewed in order to list the known genes, environmental factors, and health conditions associated with PC or involved in the carcinogenesis of the pancreas. Most of the genes listed are responsible for various well-defined cancer syndromes, such as CDKN2A (familial atypical mole-multiple melanoma, FAMMM), the mismatch repair genes (Lynch Syndrome), TP53 (Li-Fraumeni syndrome), APC (familial adenomatous polyposis), and BRCA2 (breast-ovarian familial cancer), where PC is part of the cancer spectrum of the disease. In addition, in this review I ranked known/possible risk factors extending the analysis to the hereditary pancreatitis (HP), diabetes, or to specific environmental exposures such as smoking. It appears that these factors contribute strongly to only a small proportion of PC cases. Recent work has revealed new genes somatically mutated in PC, including alterations within the pathways of Wnt/Notch and DNA mismatch repair. These new insights will help to reveal new candidate genes for the susceptibility to this disease and to better ascertain the actual contribution of the familial forms.
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PMID:Genetic predisposition and environmental risk factors to pancreatic cancer: A review of the literature. 1915 Apr 14


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