title: TP53 germline mutations in Portugal and genetic modifiers of age at cancer onset.
abstract: The Li-Fraumeni syndrome (LFS) is a rare, autosomal dominant disease caused by TP53 germline mutations. This study aimed to characterize the TP53 mutational spectrum in patients suspected to have LFS in Portugal and to evaluate the influence of the MDM2-SNP309 and TP53-72Arg variants and of telomere length on age of tumor onset. Probands were primarily selected using the classical LFS criteria (two cases) or the more sensitive Chompret Li-Fraumeni-like (LFL) criteria (13 cases), but 12 additional patients that did not comply with those LFS or LFL criteria were included in the analysis based on clinical suspicion (LFS suspects). Nine of the 27 probands (33.3%) presented germline TP53 mutations, two of them occurring de novo and two of them being novel. Three of the nine TP53 mutations were found in families that did not comply with any of the commonly used criteria for TP53 testing, leaving room to recommend the use of less stringent criteria. An association was found between the presence of the TP53-72Arg (but not the MDM2-SNP309) variant and earlier age of onset in TP53 carriers. A negative correlation between telomere length and age of cancer onset was found in patients with germline TP53 mutation, whereas no such correlation was found in controls or in patients with wild-type TP53.
authors.affiliation: Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072 Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Pinto
authors.forename: Isabel
authors.initials: I
authors.lastname: Veiga
authors.forename: Manuela
authors.initials: M
authors.lastname: Pinheiro
authors.forename: Ana
authors.initials: A
authors.lastname: Peixoto
authors.forename: Armando
authors.initials: A
authors.lastname: Pinto
authors.forename: José M
authors.initials: JM
authors.lastname: Lopes
authors.forename: Rui M
authors.initials: RM
authors.lastname: Reis
authors.forename: Carla
authors.initials: C
authors.lastname: Oliveira
authors.forename: Manuela
authors.initials: M
authors.lastname: Baptista
authors.forename: Lúcia
authors.initials: L
authors.lastname: Roque
authors.forename: Fernando
authors.initials: F
authors.lastname: Regateiro
authors.forename: Luís
authors.initials: L
authors.lastname: Cirnes
authors.forename: Robert M W
authors.initials: RM
authors.lastname: Hofstra
authors.forename: Raquel
authors.initials: R
authors.lastname: Seruca
authors.forename: Sérgio
authors.initials: S
authors.lastname: Castedo
authors.forename: Manuel R
authors.initials: MR
authors.lastname: Teixeira
mesh_terms: D017668:Age of Onset; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000453:epidemiology* / Q000235:genetics*; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D011174:Portugal; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D016615:Telomere / Q000473:pathology*
chemical_list: C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2