title: p53 compound heterozygosity in a severely affected child with Li-Fraumeni syndrome.
abstract: The Li-Fraumeni Syndrome (LFS) is a rare, dominantly inherited syndrome that features high risk of cancers in childhood and early adulthood. Affected families tend to develop bone and soft tissue sarcomas, breast cancers, brain tumors, leukemias, and adrenocortical carcinomas. In some kindreds, the genetic abnormality associated with this cancer phenotype is a heterozygous germline mutation in the p53 tumor suppressor gene. Recently, we identified one patient who presented in early childhood with multiple primary cancers and who harbored three germline p53 alterations (R156H and R267Q on the maternal allele and R290H on the paternal allele). To classify the biologic effects of these alterations, functional properties of each of the p53 mutants were examined using in vitro assays of cellular growth suppression and transcriptional activation. Each amino acid substitution conferred partial or complete loss of wild-type p53 function, but the child completed normal embryonic development. This observation has not been previously reported in a human, but is consistent with observations of normal embryogenesis in p53-deficient mice.
authors.affiliation: Division of Oncology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Quesnel
authors.forename: S
authors.initials: S
authors.lastname: Verselis
authors.forename: C
authors.initials: C
authors.lastname: Portwine
authors.forename: J
authors.initials: J
authors.lastname: Garber
authors.forename: M
authors.initials: M
authors.lastname: White
authors.forename: J
authors.initials: J
authors.lastname: Feunteun
authors.forename: D
authors.initials: D
authors.lastname: Malkin
authors.forename: F P
authors.initials: FP
authors.lastname: Li
mesh_terms: D000328:Adult; D002455:Cell Division / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004275:DNA, Ribosomal / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D016158:Genes, p53 / Q000502:physiology; D006580:Genetic Carrier Screening; D014644:Genetic Variation / Q000502:physiology; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D005810:Multigene Family; D010375:Pedigree; D012441:Saccharomyces cerevisiae / Q000235:genetics; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004275:DNA, Ribosomal