title: Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p.
abstract: Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.Arg337His, c1010G>A) is found in about 0.3% of the population of Southern Brazil. This mutation is associated with partially penetrant LFS traits and is found in the germline of patients with early cancers of the LFS spectrum unselected for familial history. To characterize the extended haplotypes carrying the mutation, we have genotyped 9 short tandem repeats on chromosome 17p in 12 trios of Brazilian p.Arg337His carriers. Results confirm that all share a common ancestor haplotype of Caucasian/Portuguese-Iberic origin, distant in about 72-84 generations (2000 years assuming a 25 years intergenerational distance) and thus pre-dating European migration to Brazil. So far, the founder p.Arg337His haplotype has not been detected outside Brazil, with the exception of two residents of Portugal, one of them of Brazilian origin. On the other hand, increased meiotic recombination in p.Arg337His carriers may account for higher than expected haplotype diversity. Further studies comparing haplotypes in populations of Brazil and of other areas of Portuguese migration are needed to understand the historical context of this mutation in Brazil.
authors.affiliation: Post-Graduate Program, Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.|Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Diego Davila
authors.initials: DD
authors.lastname: Paskulin
authors.affiliation: Post-Graduate Program, Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.|Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Juliana
authors.initials: J
authors.lastname: Giacomazzi
authors.affiliation: Department of Oncogenetics, AC Camargo Cancer Center, Sao Paulo, Brazil.
authors.forename: Maria Isabel
authors.initials: MI
authors.lastname: Achatz
authors.affiliation: Life and Health Sciences Research Institute, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.
authors.forename: Sandra
authors.initials: S
authors.lastname: Costa
authors.affiliation: Life and Health Sciences Research Institute, University of Minho, Braga, Portugal; ICVS/3B's-PT Government Associate Laboratory, Braga/Guimarães, Portugal.|Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, São Paulo, Brazil.
authors.forename: Rui Manoel
authors.initials: RM
authors.lastname: Reis
authors.affiliation: International Prevention Research Institute, Lyon and Institut Albert Bonniot/INSERM 823, Grenoble, France.
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.affiliation: Human and Medical Genetics Laboratory, Biosciences Institute, Federal University of Pará, Belém, Brazil.
authors.forename: Sidney Emanuel Batista
authors.initials: SE
authors.lastname: dos Santos
authors.affiliation: Post-Graduate Program, Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, Brazil.|Genomic Medicine Laboratory, Experimental Research Center, Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.|Medical Genetics Service), Hospital de Clinicas de Porto Alegre, Porto Alegre, Brazil.
authors.forename: Patricia
authors.initials: P
authors.lastname: Ashton-Prolla
mesh_terms: D001938:Brazil; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D019143:Evolution, Molecular; D018703:Founder Effect; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D018895:Microsatellite Repeats; D020125:Mutation, Missense; D010375:Pedigree; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53