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)

The CDKN2A gene encodes p16 (CDKN2A), a cell-cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1alpha and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis-sense mutation resulting in a methionine to isoleucine change at codon 53 (M531) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall-bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M531 change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi-site cancer families without melanoma are very unlikely to contain CDKN2A mutations.
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PMID:CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein. 938 68

The hereditary predisposition to cancer dates historically to interest piqued by physicians as well as family members wherein striking phenotypic features were shown to cluster in families, inclusive of the rather grotesque cutaneous findings in von Recklinghausen's neurofibromatosis, which date back to the sixteenth century. The search for the role of primary genetic factors was heralded by studies at the infrahuman level, particularly on laboratory mouse strains with strong susceptibility to carcinogen-induced cancer, and conversely, with resistance to the same carcinogens. These studies, developed in the 19th and 20th centuries, continue today. This article traces the historical aspects of hereditary cancer dealing with identification and ultimate molecular genetic confirmation of commonly occurring cancers, particularly of the colon in the case of familial adenomatous polyposis and its attenuated form, both due to the APC germline mutation; the Lynch syndrome due to mutations in mismatch repair genes, the most common of which were found to be MSH2, MLH1, and MSH6 germline mutations; the hereditary breast-ovarian cancer syndrome with BRCA1 and BRCA2 germline mutations; the Li-Fraumeni (SBLA) syndrome due to the p53 mutation; and the familial atypical multiple mole melanoma in association with pancreatic cancer due to the CDKN2A (p16) germline mutation. These and other hereditary cancer syndromes have been discussed in some detail relevant to their characterization, which, for many conditions, took place in the late 18th century and, in the more modern molecular genetic era, during the past two decades. Emphasis has been placed upon the manner in which improved cancer control will emanate from these discoveries.
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PMID:Inherited predisposition to cancer: a historical overview. 1526 68

The muroid rodents are the largest superfamily of mammals, containing nearly one third of all mammal species. We report on a phylogenetic study comprising 53 genera sequenced for four nuclear genes, GHR, BRCA1, RAG1, and c-myc, totaling up to 6400 nucleotides. Most relationships among the subfamilies are resolved. All four genes yield nearly identical phylogenies, differing only in five key regions, four of which may represent particularly rapid radiations. Support is very strong for a fundamental division of the mole rats of the subfamilies Spalacinae and Rhizomyinae from all other muroids. Among the other "core" muroids, a rapid radiation led to at least four distinct lineages: Asian Calomyscus, an African clade of at least four endemic subfamilies, including the diverse Nesomyinae of Madagascar, a hamster clade with maximum diversity in the New World, and an Old World clade including gerbils and the diverse Old World mice and rats (Murinae). The Deomyinae, recently removed from the Murinae, is well supported as the sister group to the gerbils (Gerbillinae). Four key regions appear to represent rapid radiations and, despite a large amount of sequence data, remain poorly resolved: the base of the "core" muroids, among the five cricetid (hamster) subfamilies, within a large clade of Sigmodontinae endemic to South America, and among major geographic lineages of Old World Murinae. Because of the detailed taxon sampling within the Murinae, we are able to refine the fossil calibration of a rate-smoothed molecular clock and apply this clock to date key events in muroid evolution. We calculate rate differences among the gene regions and relate those differences to relative contribution of each gene to the support for various nodes. The among-gene variance in support is greatest for the shortest branches. We present a revised classification for this largest but most unsettled mammalian superfamily.
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PMID:Phylogeny and divergence-date estimates of rapid radiations in muroid rodents based on multiple nuclear genes. 1537 Dec 45

Loss of heterozygosity (LOH) in several chromosomal regions is found in melanoma, and it has been partially studied in nevi. BRAF mutations are found in melanoma and nevi and in colorectal cancer are linked to mismatch repair deficiency. We studied early genetic events involved in melanomagenesis through analysis of allelic loss, microsatellite instability (MSI), and BRAF mutations. DNA extracted from microdissected cells of 22 common nevi, 23 atypical nevi, and 25 primary cutaneous melanomas were examined for LOH and MSI by polymerase chain reaction-based analysis of 24 microsatellite markers and BRAF mutation. Allelic loss index was higher in atypical nevi (0.20) and melanomas (0.27) than common nevi (0.07). LOH was frequent at 9p21, 17q21, 6q23, and 5q35 in melanoma. LOH at any of this loci occurred in 27% of common nevi, 57% of atypical nevi, and 68% of melanomas. BRAF mutations were not related to MSI presence and MSI index was not related with BRAF mutational status. Similar genetic alterations in atypical nevi and melanomas support the concept of atypical nevus as melanoma precursor. Novel deletion loci at 5q35 and 17q21 (BRCA1) in atypical nevi and melanomas were identified. Mismatch repair deficiency is not a crucial event for BRAF mutation in melanocytic tumors.
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PMID:Allelotyping, microsatellite instability, and BRAF mutation analyses in common and atypical melanocytic nevi and primary cutaneous melanomas. 1946 Dec 39

BRCA1-associated Protein 1 (BAP1)-inactivated melanocytic nevi/tumors (BIMT) have distinct morphologic features. A typical case exhibits a biphasic population of cytologically bland conventional melanocytes and a second proliferation of larger epithelioid melanocytes with abundant eosinophilic cytoplasm. The vast majority of cases harbor BRAF V600E in both components with bi-allelic inactivation of BAP1 in the epithelioid component by various molecular mechanisms resulting in loss of nuclear protein expression, which can be demonstrated by immunohistochemistry. We present a case of BIMT with histopathologic features highly suggestive of this entity but unexpected retention of nuclear expression of the BAP1 protein. Subsequent molecular tests showed heterozygous loss of the BAP1 locus on the short arm of chromosome 3 (3p21.1) by chromosomal microarray analysis (CMA) and a suspected c.505C>T p.H169Y pathogenic variant identified by DNA sequencing that was subsequently confirmed by primer-specific SNaPshot mini-sequencing. In light of the heterozygous deletion of BAP1, this variant in the remaining allele encodes a catalytically inactive BAP1 mutant protein as shown in functional studies. The presence of a nonfunctional allele within the nucleus combined with a heterozygous deletion of BAP1 explains the clear and characteristic BIMT morphology observed by histopathology. This case underlines the potential importance of molecular diagnostics when protein expression studies do not correlate with morphology.
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PMID:A case of molecularly confirmed BAP1 inactivated melanocytic tumor with retention of immunohistochemical expression: A confounding factor. 3189 22