Super-Transactivation TP53 Variant in the Germline of a Family with Li-Fraumeni Syndrome.
Li-Fraumeni Syndrome (LFS) is a rare autosomal dominant familial cancer syndrome, characterized by multiple malignancies and frequent germline alterations in TP53. In this study, we highlight four unclassified exonic TP53 variants detected in patients with a suspected diagnosis of LFS. Most intriguing was the discovery of a "super-transactivation" variant within Exon 10 of TP53 (c.1079G>T/p.G360V). Functional analysis of this novel variant revealed a paradoxical "super-transactivation" effect on tp53 response elements and a corresponding tumor suppressive effect on colony formation and apoptosis. While unlikely to be disease-causing, we propose that this variant may represent a novel tp53 polymorphism and potential phenotypic modifier in LFS. In the future, the enhanced transactivation effects of p.G360V-tp53 may also prove useful in designing more efficacious tp53-based gene therapies.
Department of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Department of Molecular Genetics and Microbiology, University of Toronto, Toronto, Canada.
Badr
B
Id Said
Department of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Canada.|Department of Molecular Genetics and Microbiology, University of Toronto, Toronto, Canada.
Han
H
Kim
Department of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Department of Molecular Genetics and Microbiology, University of Toronto, Toronto, Canada.
James
J
Tran
Department of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Canada.|Department of Molecular Genetics and Microbiology, University of Toronto, Toronto, Canada.
Ana
A
Novokmet
Department of Pediatrics, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Canada.|Department of Medical Biophysics, University of Toronto, Toronto, Canada.|Department of Pediatrics, University of Toronto, Toronto, Canada.|Department of Molecular Genetics and Microbiology, University of Toronto, Toronto, Canada.
David
D
Malkin
D000328:Adult; D002460:Cell Line; D002648:Child; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53
Li-Fraumeni Syndrome; gene therapy; p53; single nucleotide polymorphism