title: Founding mutations and Alu-mediated recombination in hereditary colon cancer.
abstract: By screening members of Finnish families displaying hereditary nonpolyposis colorectal cancer (HNPCC) for predisposing germline mutations in MSH2 and MLH1, we show that two mutations in MLH1 together account for 63% (19/30) of kindreds meeting international diagnostic criteria. Mutation 1, originally detected as a 165-base pair deletion in MLH1 cDNA comprising exon 16, was shown to consist of a 3.5-kilobase genomic deletion most likely resulting from Alu-mediated recombination. Mutation 2 destroys the splice acceptor site of exon 6. A simple diagnostic test based on polymerase chain reaction was designed for both mutations. Our results show that these two ancestral founding mutations account for a majority of Finnish HNPCC kindreds and represent the first report of Alu-mediated recombination causing a prevalent, dominantly inherited predisposition to cancer.
authors.affiliation: Department of Medical Genetics, University of Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Nyström-Lahti
authors.forename: P
authors.initials: P
authors.lastname: Kristo
authors.forename: N C
authors.initials: NC
authors.lastname: Nicolaides
authors.forename: S Y
authors.initials: SY
authors.lastname: Chang
authors.forename: L A
authors.initials: LA
authors.lastname: Aaltonen
authors.forename: A L
authors.initials: AL
authors.lastname: Moisio
authors.forename: H J
authors.initials: HJ
authors.lastname: Järvinen
authors.forename: J P
authors.initials: JP
authors.lastname: Mecklin
authors.forename: K W
authors.initials: KW
authors.lastname: Kinzler
authors.forename: B
authors.initials: B
authors.lastname: Vogelstein
mesh_terms: D001483:Base Sequence; D003001:Cloning, Molecular; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D004198:Disease Susceptibility; D005091:Exons; D005387:Finland / Q000453:epidemiology; D018703:Founder Effect; D005799:Genes, Dominant; D006801:Humans; D007438:Introns; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011995:Recombination, Genetic; D012091:Repetitive Sequences, Nucleic Acid; D017422:Sequence Analysis, DNA