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

Abstract

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.

• Authors: M Meier, M L den Boer, A G Hall, J A E Irving, M Passier, L Minto, E R van Wering, G E Janka-Schaub, R Pieters
• Journal: Leukemia (Leukemia) Vol. 19 Issue 11 Pg. 1887-95 (Nov 2005) ISSN: 0887-6924 [Print] England
• PMID: 16167060 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibiotics, Antineoplastic
• Cell Cycle Proteins
• DNA-Binding Proteins
• Tumor Suppressor Proteins
• ATM protein, human
• Ataxia Telangiectasia Mutated Proteins
• Protein Serine-Threonine Kinases
• Daunorubicin

Topics

• Adolescent
• Adult
• Aged
• Antibiotics, Antineoplastic (pharmacology)
• Ataxia Telangiectasia Mutated Proteins
• Case-Control Studies
• Cell Cycle Proteins (genetics)
• Child
• Child, Preschool
• DNA-Binding Proteins (genetics)
• Daunorubicin (pharmacology)
• Disease-Free Survival
• Drug Resistance, Neoplasm (genetics)
• Female
• Gene Expression Profiling
• Genetic Predisposition to Disease
• Humans
• Infant
• Leukemia-Lymphoma, Adult T-Cell (drug therapy, genetics, pathology)
• Leukocyte Count
• Male
• Middle Aged
• Phenotype
• Polymorphism, Single Nucleotide
• Prognosis
• Protein Serine-Threonine Kinases (genetics)
• Reverse Transcriptase Polymerase Chain Reaction
• Risk Factors
• Tumor Suppressor Proteins (genetics)