Relation between genetic variants of the ataxia telangiectasia-mutated ( ) gene, drug resistance, clinical outcome and predisposition to childhood T-lineage acute lymphoblastic leukaemia

• Published in: Leukemia Vol. 19; no. 11; pp. 1887 - 1895
• Main Authors: MEIER, M, DEN BOER, M. L, HALL, A. G, IRVING, J. A. E, PASSIER, M, MINTO, L, VAN WERING, E. R, JANKA-SCHAUB, G. E, PIETERS, R
• Format: Journal Article
• Language: English
• Published: London Nature Publishing 01.11.2005; Nature Publishing Group
• Subjects: Acute lymphoblastic leukemia; Adolescent; Adult; Aged; Antibiotics, Antineoplastic - pharmacology; Ataxia; Ataxia telangiectasia; Ataxia telangiectasia mutated protein; Ataxia Telangiectasia Mutated Proteins; Biological and medical sciences; Blood; Case-Control Studies; Cell cycle; Cell Cycle Proteins - genetics; Child; Child, Preschool; Children; Clinical outcomes; Daunorubicin; Daunorubicin - pharmacology; Disease-Free Survival; DNA-Binding Proteins - genetics; Drug resistance; Drug Resistance, Neoplasm - genetics; Exons; Female; Gene Expression Profiling; Genetic diversity; Genetic Predisposition to Disease; Genetic variance; Genotype & phenotype; Health risks; Hematologic and hematopoietic diseases; Hematology; Humans; Infant; Kinases; Leukemia; Leukemia-Lymphoma, Adult T-Cell - drug therapy; Leukemia-Lymphoma, Adult T-Cell - genetics; Leukemia-Lymphoma, Adult T-Cell - pathology; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Leukocyte Count; Leukocytes; Lymphocytes T; Male; Medical research; Medical sciences; Middle Aged; Mutation; Nucleotides; Oncology; Patients; Pediatrics; Phenotype; Phenotypes; Polymorphism; Polymorphism, Single Nucleotide; Prognosis; Protein-Serine-Threonine Kinases - genetics; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; Tumor Suppressor Proteins - genetics; Netherlands; Human; Treatment resistance; Prognosis; Hematology; Lymphoproliferative syndrome; Acute; Genetic variant; Predisposition; Malignant hemopathy; Acute lymphocytic leukemia; Child
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/sj.leu.2403943

The T-lineage phenotype in children with acute lymphoblastic leukaemia (ALL) is associated with in vitro drug resistance and a higher relapse-risk compared to a precursor B phenotype. Our study was aimed to investigate whether mutations in the ATM gene occur in childhood T-lineage acute lymphoblastic leukaemia (T-ALL) that are linked to drug resistance and clinical outcome. In all, 20 different single nucleotide substitutions were found in 16 exons of ATM in 62/103 (60%) T-ALL children and 51/99 (52%, P = 0.21) controls. Besides the well-known polymorphism D1853N, five other alterations (S707P, F858L, P1054R, L1472W, Y1475C) in the coding part of ATM were found. These five coding alterations seem to occur more frequently in T-ALL (13%) than controls (5%, P = 0.06), but did not associate with altered expression levels of ATM or in vitro resistance to daunorubicin. However, T-ALL patients carrying these five coding alterations presented with a higher white blood cell count at diagnosis (P = 0.05) and show an increased relapse-risk (5-year probability of disease-free survival (pDFS) = 48%) compared to patients with other alterations or wild-type ATM (5-year pDFS = 76%, P = 0.05). The association between five coding ATM alterations in T-ALL, their germline presence, white blood cell count and unfavourable outcome may point to a role for ATM in the development of T-ALL in these children.