title: Detailed haplotype analysis at the TP53 locus in p.R337H mutation carriers in the population of Southern Brazil: evidence for a founder effect.
abstract: Due to patterns of migration, selection, and population expansion, founder effects are common among humans. In Southern Brazil, a recurrent TP53 mutation, p.R337H, is detected in families with cancer predisposition. We have used whole locus resequencing and high-density single nucleotide polymorphism (SNP) genotyping to refine TP53 locus haplotype definitions. Haplotyping of 12 unrelated p.R337H carriers using a set of 29 tag SNPs, revealed that all subjects carried the same haplotype, and presence of the mutation on this haplotype was confirmed by allele-specific PCR. The probability that this haplotype occurs independently in all index cases was of 3.1x10(-9), demonstrating a founder effect. Analysis of the patterns of 103 tumors diagnosed in 12 families showed that the presence of p.R337H is associated with multiple cancers of the Li-Fraumeni Syndrome (LFS) spectrum, with relatively low penetrance before the age of 30 but a lifetime risk comparable to classical LFS. The p.R337H families are mostly distributed along a road axis historically known as the main route used by merchants of Portuguese origin in the XVIII and XIX century. This historical circumstance and the relatively low penetrance before the age of 30 may have contributed to the maintenance of this pathogenic mutation in a large, open population.
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, Rhône, France.
authors.forename: Sonia
authors.initials: S
authors.lastname: Garritano
authors.forename: Federica
authors.initials: F
authors.lastname: Gemignani
authors.forename: Edenir Inez
authors.initials: EI
authors.lastname: Palmero
authors.forename: Magali
authors.initials: M
authors.lastname: Olivier
authors.forename: Ghyslaine
authors.initials: G
authors.lastname: Martel-Planche
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.forename: Laurence
authors.initials: L
authors.lastname: Brugiéres
authors.forename: Fernando Regla
authors.initials: FR
authors.lastname: Vargas
authors.forename: Ricardo Renzo
authors.initials: RR
authors.lastname: Brentani
authors.forename: Patricia
authors.initials: P
authors.lastname: Ashton-Prolla
authors.forename: Stefano
authors.initials: S
authors.lastname: Landi
authors.forename: Sean V
authors.initials: SV
authors.lastname: Tavtigian
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.forename: Maria Isabel W
authors.initials: MI
authors.lastname: Achatz
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution / Q000235:genetics*; D001483:Base Sequence; D001938:Brazil; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D018703:Founder Effect; D056426:Genetic Loci / Q000235:genetics*; D005828:Genetics, Population; D006239:Haplotypes / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007223:Infant; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
chemical_list: D016159:Tumor Suppressor Protein p53