title: The TP53 mutational spectrum and frequency of CHEK2*1100delC in Li-Fraumeni-like kindreds.
abstract: Li-Fraumeni syndrome (LFS) is a dominantly inherited cancer predisposition syndrome characterized by a wide spectrum of neoplasms occurring at young age. Germline mutations in the TP53 tumor suppressor gene have been identified in approximately 71 of LFS patients and 22 of Li-Fraumeni-like (LFL) patients. Mutations within the cell cycle checkpoint gene CHEK2 have also been reported in some patients with LFS, LFL, and phenotypically suggestive of LFS (PS-LFS) not carrying a TP53 mutation. In this study, we show that 7 of the 23 patients with LFS/LFL tested positive for deleterious mutations in p53. Fifteen of the remaining sixteen were not found to carry the CHEK2* 1100delCmutation. These results indicate that CHEK2*1100delC is not a common cause of LFS, LFL, or PS-LFS in North American kindreds not carrying a TP53 mutation. Of note, two patients were found to carry p53* R72P, which is of unknown clinical significance. Lack of segregation of this allele in one of these kindreds provides strong evidence that the R72P allele is not disease-causing. While mutations in p53 account for a proportion of patients with LFS/LFL, future studies are needed to determine if other genes are responsible for LFS/LFL families not carrying germline p53 mutations.
authors.affiliation: Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10021, USA.
authors.forename: Rina
authors.initials: R
authors.lastname: Siddiqui
authors.forename: Kenan
authors.initials: K
authors.lastname: Onel
authors.forename: Flavia
authors.initials: F
authors.lastname: Facio
authors.forename: Kedoudja
authors.initials: K
authors.lastname: Nafa
authors.forename: Louis Robles
authors.initials: LR
authors.lastname: Diaz
authors.forename: Noah
authors.initials: N
authors.lastname: Kauff
authors.forename: Helen
authors.initials: H
authors.lastname: Huang
authors.forename: Mark
authors.initials: M
authors.lastname: Robson
authors.forename: Nathan
authors.initials: N
authors.lastname: Ellis
authors.forename: Kenneth
authors.initials: K
authors.lastname: Offit
mesh_terms: D000293:Adolescent; D000328:Adult; D064447:Checkpoint Kinase 2; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D016158:Genes, p53; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*
chemical_list: D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases