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Blood, 1 January 2009, Vol. 113, No. 1, pp. 100-107.
Prepublished online as a Blood First Edition Paper on October 6, 2008; DOI 10.1182/blood-2008-07-166801.
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Submitted July 9, 2008
Accepted September 8, 2008
A comprehensive analysis of the CDKN2A gene in childhood acute lymphoblastic leukaemia reveals genomic deletion, copy number neutral loss of heterozygosity and association with specific cytogenetic subgroups
Sarina Sulong, Anthony V Moorman*, Julie AE Irving, Jonathan C Strefford, Zoe J Konn, Marian C Case, Lynne Minto, Kerry E Barber, Helen Parker, Sarah L Wright, Adam RM Stewart, Simon Bailey, Nick P Bown, Andrew G Hall, and Christine J Harrison
Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, United Kingdom
Cancer Genomics Group, Cancer Sciences Division, University of Southampton, Southampton, United Kingdom
Leukaemia Research Cytogenetics Group, University of Southampton, Southampton, United Kingdom
Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom
NHS Northern Genetics Service, Newcastle upon Tyne, United Kingdom
* Corresponding author; email: anthony.moorman{at}ncl.ac.uk.
Inactivation of the tumour suppressor gene, CDKN2A, can occur by deletion, methylation or mutation. We assessed the principal mode of inactivation in childhood ALL and frequency in biologically relevant subgroups. CDKN2A mutation or methylation was rare whereas genomic deletion occurred in 21% BCP-ALL and 50% T-ALL patients. SNP arrays revealed copy number neutral (CNN) LOH in 8% patients. Array CGH (aCGH) demonstrated that the mean size of deletions was 14.8Mb and biallelic deletions comprised a large and small deletion (mean sizes 23.3Mb & 1.4Mb). Among 86 patients tested by FISH and SNP/aCGH, only two small deletions (0.025Mb & 0.05Mb) were below the resolution of detection by FISH. Patients with high hyperdiploidy, ETV6-RUNX1 or 11q23/MLL rearrangements had low rates of deletion (11%, 15%, 13%) whereas patients with t(9;22), t(1;19), TLX3 or TLX1 rearrangements had higher frequencies (61%, 42%, 78% and 89%). In conclusion, CDKN2A deletion is a significant secondary abnormality in childhood ALL strongly correlated with phenotype and genotype. The variation in the incidence of CDKN2A deletions by cytogenetic subgroup may explain its inconsistent association with outcome. The discovery of CNN LOH without apparent CDKN2A inactivation suggests the presence of other relevant genes in this region. The trials described in this paper are registered with ISRCTN, http://www.controlled-trials.com/isrctn/: ALL2003 under ID no. 07355119, ALL97 under ID no. 26727615, and UKALLXI under ID no. 16757172.
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