title: p53 centrosomal localization diagnoses ataxia-telangiectasia homozygotes and heterozygotes.
abstract: Ataxia-telangiectasia (A-T) is an autosomal recessive neurodegenerative disorder characterized by radiosensitivity, genomic instability, and predisposition to cancer. A-T is caused by biallelic mutations in the ataxia-telangiectasia mutated (ATM) gene, but heterozygous carriers, though apparently healthy, are believed to be at increased risk for cancer and more sensitive to ionizing radiation than the general population. Despite progress in functional and sequencing-based assays, no straightforward, rapid, and inexpensive test is available for the identification of A-T homozygotes and heterozygotes, which is essential for diagnosis, genetic counseling, and carrier prediction. The oncosuppressor p53 prevents genomic instability and centrosomal amplification. During mitosis, p53 localizes at the centrosome in an ATM-dependent manner. We capitalized on the latter finding and established a simple, fast, minimally invasive, reliable, and inexpensive test to determine mutant ATM zygosity. The percentage of mitotic lymphoblasts or PBMCs bearing p53 centrosomal localization clearly discriminated among healthy donors (>75%), A-T heterozygotes (40%-56%), and A-T homozygotes (<30%). The test is specific for A-T, independent of the type of ATM mutations, and recognized tumor-associated ATM polymorphisms. In a preliminary study, our test confirmed that ATM is a breast cancer susceptibility gene. These data open the possibility of cost-effective, early diagnosis of A-T homozygotes and large-scale screenings for heterozygotes.
authors: Department of Experimental Oncology, Regina Elena National Cancer Institute, Rome, Italy.
authors: Andrea
authors: A
authors: Prodosmo
authors: Andrea
authors: A
authors: De Amicis
authors: Cecilia
authors: C
authors: Nisticò
authors: Mario
authors: M
authors: Gabriele
authors: Giuliana
authors: G
authors: Di Rocco
authors: Laura
authors: L
authors: Monteonofrio
authors: Maria
authors: M
authors: Piane
authors: Enrico
authors: E
authors: Cundari
authors: Luciana
authors: L
authors: Chessa
authors: Silvia
authors: S
authors: Soddu
mesh_terms: D000328:Adult; D000368:Aged; D001260:Ataxia Telangiectasia / Q000175:diagnosis* / Q000235:genetics; D064007:Ataxia Telangiectasia Mutated Proteins; D001483:Base Sequence; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D002478:Cells, Cultured; D018385:Centrosome / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003937:Diagnosis, Differential; D060005:Genotyping Techniques; D006579:Heterozygote; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D008856:Microscopy, Fluorescence; D008875:Middle Aged; D008938:Mitosis; D025202:Molecular Diagnostic Techniques; D020125:Mutation, Missense; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases