From the Department of Pediatrics and Developmental Biology, Postgraduate Medical School, Tokyo Medical and Dental University; the Molecular Oncology Division and the Radiobiology Division, National Cancer Center Research Institute; the Department of Hematology/Oncology, National Center for Child Health and Development; the Department of Pediatrics, Kyorin University; the Department of Pediatrics, Oume Municipal Hospital, Tokyo, Japan; the Department of Experimental Oncology, Istituto Nazionale Tumori, Milan, Italy; the Department of Experimental Medicine and Pathology, University "La Sapienza," Rome, Italy; the Department of Biochemistry, Nagoya City University Medical School, Nagoya, Japan; the Department of Pediatrics, Showa University of Medical School, Kanagawa, Japan; the Department of Pediatrics, Nagoya University, Nagoya, Japan; and the Section of Pediatrics, National Kyushu Cancer Center, Fukuoka, Japan.
There are conflicting reports about the involvement of single nucleotide polymorphisms (SNPs) of the ataxia telangiectasia mutated (ATM) gene with cancer, and the consequences of these SNPs for ATM function remain unclear. We therefore sought to identify SNPs of the ATM gene in pediatric Hodgkin disease (HD) and to analyze ATM function in cells from patients with these SNPs. We have identified SNPs of the ATM gene in 5 of 14 children (S1455R, n = 1; H1380Y, n = 1; N1650S, n = 2; and I709I, n = 1). One patient had nonsense-associated altered splicing of the ATM gene. Lymphoblastoid cell lines expressing the S1455R and N1650S exhibited defective ATM-mediated p53 phosphorylation and Chk2 activation; cells expressing the H1380Y exhibited defective c-Abl activation after X-irradiation. Expression of the N1650S in ATM-null fibroblasts conferred only partial hyperradiosensitivity. Furthermore, the introduction of N1650S ATM into U2OS cells, which express wild-type ATM, showed reduced p53-Ser15 phosphorylation, suggesting a dominant-negative effect of the N1650S over the wild-type ATM protein. We conclude that the rare polymorphic variants of the ATM gene that we identified in children with HD encode functionally abnormal proteins, and we discuss the possible genetic risk factors for childhood HD.
Identification of a Small Molecular Anti-HIV-1 Compound that Interferes with Formation of the Fusion -active gp41 Core
Metabolomic Identification of Novel Biomarkers of Myocardial Ischemia
Identification and Characterization of Two Genes (MIP-1;, VE-CADHERIN) Implicated in Acute Rejection in Human Heart Transplantation
Identification of Penumbra and Infarct in Acute Ischemic Stroke Using Computed Tomography Perfusion–Derived Blood Flow and Blood Volume Measurements
Identification of Culprit Lesions After Transient Ischemic Attack by Combined 18F Fluorodeoxyglucose Positron-Emission Tomography and High-Resolution Magnetic Resonance Imaging
Significance of Susceptibility Vessel Sign on T2-Weighted Gradient Echo Imaging for Identification of Stroke Subtypes
Identification of Embolic Stroke Patterns by Diffusion-Weighted MRI in Clinically Defined Lacunar Stroke Syndromes
Helical CT with CT Angiography in Assessing Periampullary Neoplasms: Identification of Vascular Invasion
Identification of Attenuated Variants of HIV-1 Circulating Recombinant Form 01_AE That Are Associated with Slow Disease Progression Due to Gross Genetic Alterations in the nef/Long Terminal Repeat Seq
Identification of the Optimal Structure Required for a Shiga Toxin Neutralizer with Oriented Carbohydrates to Function in the Circulation