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dc.contributor.authorHewitt, Chelsee
dc.contributor.authorLee Wu, Chu
dc.contributor.authorEvans, D Gareth R
dc.contributor.authorHowell, Anthony
dc.contributor.authorElles, Robert G
dc.contributor.authorJordan, Richard
dc.contributor.authorSloan, Philip
dc.contributor.authorRead, Andrew P
dc.contributor.authorThakker, Nalin
dc.date.accessioned2009-09-15T14:53:46Z
dc.date.available2009-09-15T14:53:46Z
dc.date.issued2002-05-15
dc.identifier.citationGermline mutation of ARF in a melanoma kindred. 2002, 11 (11):1273-9 Hum. Mol. Genet.en
dc.identifier.issn0964-6906
dc.identifier.pmid12019208
dc.identifier.urihttp://hdl.handle.net/10541/81137
dc.description.abstractFamilial melanoma predisposition is associated with germline mutations at the CDKN2A/ARF locus in up to 40% of families. The exact role of the two proteins encoded by this complex locus in this predisposition is unclear. Most mutations affect either CDKN2A only or products of both genes. Recently a deletion affecting ARF-specific exon 1beta was reported in a family with melanoma and neural tumours. However, the possibility of this deletion also altering the CDKN2A transcript could not be excluded. More convincingly, a 16 base pair insertion in exon 1beta has been reported in an individual with multiple melanomas suggesting a direct role for ARF in melanoma predisposition. We report here a splice mutation in exon 1beta in a family with melanoma that results in ARF haploinsufficiency. The mutation was observed in a mother and daughter with melanoma. A sibling of the mother with breast cancer also had this mutation. Analysis of the melanoma from one individual revealed a 62 bp deletion in exon 3 of the wildtype allele and loss of the mutant allele; these somatic changes would affect both CDKN2A and ARF. These somatic events suggest that concomitant inactivation of both ARF and CDKN2A may be necessary for melanoma development and that mutations in ARF and CDKN2A possibly confer different levels of susceptibility to melanoma, with the former associated with lesser predisposition. In this situation, the events follow a 'three-hit' model as observed in tumours from FAP patients with an attenuated phenotype. Overall, the data suggest a direct role for ARF haploinsufficiency in melanoma predisposition and co-operation between ARF and CDKN2A in tumour formation, consistent with recent observations in Cdkn2a-specific knockout mice.
dc.language.isoenen
dc.subjectBreast Canceren
dc.subjectCancer DNAen
dc.subjectTumour Suppressor Proteinsen
dc.subjectTumour Suppressor Protein p14ARFen
dc.subject.meshAdult
dc.subject.meshBase Sequence
dc.subject.meshBreast Neoplasms
dc.subject.meshCyclin-Dependent Kinase Inhibitor p16
dc.subject.meshDNA, Neoplasm
dc.subject.meshFemale
dc.subject.meshGenetic Predisposition to Disease
dc.subject.meshGerm-Line Mutation
dc.subject.meshHumans
dc.subject.meshMale
dc.subject.meshMelanoma
dc.subject.meshMiddle Aged
dc.subject.meshMolecular Sequence Data
dc.subject.meshMutation, Missense
dc.subject.meshPedigree
dc.subject.meshTumor Suppressor Protein p14ARF
dc.subject.meshTumor Suppressor Proteins
dc.titleGermline mutation of ARF in a melanoma kindred.en
dc.typeArticleen
dc.contributor.departmentUniversity of Manchester Department of Medical Genetics and Regional Genetic Service, Central Manchester Healthcare Trust, St. Mary's Hospital, Manchester, M13 OJH, UK.en
dc.identifier.journalHuman Molecular Geneticsen
html.description.abstractFamilial melanoma predisposition is associated with germline mutations at the CDKN2A/ARF locus in up to 40% of families. The exact role of the two proteins encoded by this complex locus in this predisposition is unclear. Most mutations affect either CDKN2A only or products of both genes. Recently a deletion affecting ARF-specific exon 1beta was reported in a family with melanoma and neural tumours. However, the possibility of this deletion also altering the CDKN2A transcript could not be excluded. More convincingly, a 16 base pair insertion in exon 1beta has been reported in an individual with multiple melanomas suggesting a direct role for ARF in melanoma predisposition. We report here a splice mutation in exon 1beta in a family with melanoma that results in ARF haploinsufficiency. The mutation was observed in a mother and daughter with melanoma. A sibling of the mother with breast cancer also had this mutation. Analysis of the melanoma from one individual revealed a 62 bp deletion in exon 3 of the wildtype allele and loss of the mutant allele; these somatic changes would affect both CDKN2A and ARF. These somatic events suggest that concomitant inactivation of both ARF and CDKN2A may be necessary for melanoma development and that mutations in ARF and CDKN2A possibly confer different levels of susceptibility to melanoma, with the former associated with lesser predisposition. In this situation, the events follow a 'three-hit' model as observed in tumours from FAP patients with an attenuated phenotype. Overall, the data suggest a direct role for ARF haploinsufficiency in melanoma predisposition and co-operation between ARF and CDKN2A in tumour formation, consistent with recent observations in Cdkn2a-specific knockout mice.


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