1. ¹Department of Paediatric Oncology/Haematology, Erasmus MC/Sophia Children's Hospital, Erasmus University Medical Centre, Rotterdam, The Netherlands
2. ²Leukaemia Research Group, Northern Institute for Cancer Research, Medical School, University of Newcastle upon Tyne, Newcastle upon Tyne, UK
3. ³DCOG, Dutch Childhood Oncology Group, The Hague, The Netherlands
4. ⁴COALL, German Cooperative Study Group for Childhood Acute Lymphoblastic Leukaemia, Children's University Hospital, Hamburg, Germany

Correspondence: Dr ML den Boer, Erasmus MC – Department of Paediatric Oncology/Haematology, Sophia Children's Hospital, Dr Molewaterplein 60, Rotterdam 3015 GJ, The Netherlands; Fax: +31 10 4089433; E-mail: m.l.denboer@erasmusmc.nl

Received 7 July 2005; Accepted 10 August 2005; Published online 15 September 2005.

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.