title: IVS10-6T>G, an ancient ATM germline mutation linked with breast cancer.
abstract: Patients with autosomal recessive multisystemic disorder ataxia-telangiectasia are homozygous or compound heterozygous for mutations in the ataxia-telangiectasia mutated (ATM) gene. Heterozygous carriers of an ATM germline mutation have an increased susceptibility for breast cancer. The subject of this study is one particular germline mutation, the ATM exon 11 splice-site mutation IVS10-6T>G, that has been identified as being associated with an increased risk for breast cancer both in the general population and in high-risk breast cancer families. We investigated the natural history of this mutation, i.e., whether it is frequently arising de novo in a population, or whether it can be traced back to a single ancient mutational event. Genotyping of a number of polymorphic markers (two extragenic and two intragenic microsatellite loci, a single nucleotide insertion/deletion polymorphism, and a dinucleotide insertion/deletion polymorphism) was performed in 18 samples from different populations carrying the IVS10-6T>G mutation (17 unrelated breast cancer patients who were heterozygous carriers of this mutation and a single A-T patient who was homozygous for the IVS10-6T>G mutation). The same markers were also genotyped among 39 unrelated healthy individuals without this mutation. Haplotype analyses revealed one common ancestor in all mutation carriers. By means of a maximum likelihood method, we estimated the age of this mutation to be approximately 2,000 generations. We provide evidence that the IVS10-6T>G mutation occurred only once during human evolution, at least 50,000 years ago. Our results predict that this mutation could be widely distributed across Europe and, probably, the Middle East and Western Asia.
authors.affiliation: Department of Experimental Therapy, The Netherlands Cancer Institute, Amsterdam, The Netherlands. a.broeks@nki.nl
authors.forename: Annegien
authors.initials: A
authors.lastname: Broeks
authors.forename: Jos H M
authors.initials: JH
authors.lastname: Urbanus
authors.forename: Peter
authors.initials: P
authors.lastname: de Knijff
authors.forename: Peter
authors.initials: P
authors.lastname: Devilee
authors.forename: Marion
authors.initials: M
authors.lastname: Nicke
authors.forename: Karin
authors.initials: K
authors.lastname: Klöpper
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.forename: Arno N
authors.initials: AN
authors.lastname: Floore
authors.forename: Laura J
authors.initials: LJ
authors.lastname: van't Veer
mesh_terms: D017398:Alternative Splicing / Q000235:genetics; D001260:Ataxia Telangiectasia / Q000235:genetics*; D064007:Ataxia Telangiectasia Mutated Proteins; D001943:Breast Neoplasms / Q000235:genetics*; D018797:Cell Cycle Proteins; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D005260:Female; D018703:Founder Effect; D005787:Gene Frequency; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D025521:Tumor Suppressor Proteins
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; D004247:DNA; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases