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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. This Article Full Text (PDF) All Versions of this Article: blood-2008-07-166801v1 113/1/100    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Sulong, S. Articles by Harrison, C. J Search for Related Content PubMed PubMed Citation Articles by Sulong, S. Articles by Harrison, C. J Social Bookmarking                   What's this?  Previous Article  |  Next Article  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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: A. K. Fielding, J. M. Rowe, S. M. Richards, G. Buck, A. V. Moorman, I. J. Durrant, D. I. Marks, A. K. McMillan, M. R. Litzow, H. M. Lazarus, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993 Blood, May 7, 2009; 113(19): 4489 - 4496. [Abstract] [Full Text] [PDF]

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