2.50
Hdl Handle:
http://hdl.handle.net/10541/81137
Title:
Germline mutation of ARF in a melanoma kindred.
Authors:
Hewitt, Chelsee; Lee Wu, Chu; Evans, D Gareth R; Howell, Anthony ( 0000-0002-3879-5991 ) ; Elles, Robert G; Jordan, Richard; Sloan, Philip; Read, Andrew P; Thakker, Nalin
Abstract:
Familial 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.
Affiliation:
University of Manchester Department of Medical Genetics and Regional Genetic Service, Central Manchester Healthcare Trust, St. Mary's Hospital, Manchester, M13 OJH, UK.
Citation:
Germline mutation of ARF in a melanoma kindred. 2002, 11 (11):1273-9 Hum. Mol. Genet.
Journal:
Human Molecular Genetics
Issue Date:
15-May-2002
URI:
http://hdl.handle.net/10541/81137
PubMed ID:
12019208
Type:
Article
Language:
en
ISSN:
0964-6906
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
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.en
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

Related articles on PubMed

All Items in Christie are protected by copyright, with all rights reserved, unless otherwise indicated.