title: The M53I mutation in CDKN2A is a founder mutation that predominates in melanoma patients with Scottish ancestry.
abstract: Germline mutations in the tumor suppressor gene CDKN2A have been shown to predispose to cutaneous malignant melanoma. The M53I mutation is the most common CDKN2A mutation identified in Scottish melanoma patients and is also found in a small number of families in other countries. The aim of this study was to determine whether the occurrence of this mutation is due to a common ancestor originating from Scotland, and if so, to estimate how long ago the mutation arose. We examined 18 families carrying the M53I mutation: six from Scotland, five from Canada, four from Australia, and three from America. Haplotypes derived from segregation of seven informative microsatellite markers flanking CDKN2A were constructed in each family. Our findings show that 14 of 18 families carry a common ancestral haplotype on which the mutation arose approximately 88 generations ago (1-LOD-unit support interval 44-198 generations). This haplotype is very rare in controls, which supports the idea that it is a common founder mutation haplotype. The four M53I families that do not share the consensus haplotype may in fact have arisen from the same founder, but this is potentially obscured by presumed replication slippage for some of the microsatellite markers tested.
authors.affiliation: Duncan Guthrie Institute, Glasgow, UK. j.lang@clinmed.gla.ac.uk
authors.forename: Julie
authors.initials: J
authors.lastname: Lang
authors.forename: Nicholas
authors.initials: N
authors.lastname: Hayward
authors.forename: David
authors.initials: D
authors.lastname: Goldgar
authors.forename: Hensin
authors.initials: H
authors.lastname: Tsao
authors.forename: David
authors.initials: D
authors.lastname: Hogg
authors.forename: Jane
authors.initials: J
authors.lastname: Palmer
authors.forename: Mitchell
authors.initials: M
authors.lastname: Stark
authors.forename: Edward S
authors.initials: ES
authors.lastname: Tobias
authors.forename: Rona
authors.initials: R
authors.lastname: MacKie
mesh_terms: D000328:Adult; D000569:Americas; D001315:Australia; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D018703:Founder Effect; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D008545:Melanoma / Q000208:ethnology / Q000235:genetics*; D018895:Microsatellite Repeats; D008875:Middle Aged; D010375:Pedigree; D012606:Scotland; D012878:Skin Neoplasms / Q000208:ethnology / Q000235:genetics*; D044465:White People
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16