title: Germline mutation of ARF in a melanoma kindred.
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.
authors.affiliation: University of Manchester Department of Medical Genetics and Regional Genetic Service, Central Manchester Healthcare Trust, St. Mary's Hospital, Manchester, M13 OJH, UK.
authors.forename: Chelsee
authors.initials: C
authors.lastname: Hewitt
authors.forename: Chu
authors.initials: C
authors.lastname: Lee Wu
authors.forename: Gareth
authors.initials: G
authors.lastname: Evans
authors.forename: A
authors.initials: A
authors.lastname: Howell
authors.forename: Robert G
authors.initials: RG
authors.lastname: Elles
authors.forename: Richard
authors.initials: R
authors.lastname: Jordan
authors.forename: Philip
authors.initials: P
authors.lastname: Sloan
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Read
authors.forename: Nalin
authors.initials: N
authors.lastname: Thakker
mesh_terms: D000328:Adult; D001483:Base Sequence; D001943:Breast Neoplasms / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D004273:DNA, Neoplasm; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D025803:Tumor Suppressor Protein p14ARF; D025521:Tumor Suppressor Proteins