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13Q Deletion Anatomy and Disease Progression in Patients with Chronic Lymphocytic Leukemia

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13Q Deletion Anatomy and Disease Progression in Patients with Chronic Lymphocytic Leukemia Leukemia (2011) 25, 489–497 & 2011 Macmillan Publishers Limited All rights reserved 0887-6924/11 www.nature.com/leu ORIGINAL ARTICLE 13q deletion anatomy and disease progression in patients with chronic lymphocytic leukemia H Parker1,7, MJJ Rose-Zerilli1,7, A Parker2, T Chaplin3, R Wade4, A Gardiner2, M Griffiths5, A Collins6, BD Young3, DG Oscier2,8 and JC Strefford1,8 1Cancer Genomics Group, Cancer Sciences Division, School of Medicine, University of Southampton, Southampton, UK; 2Department of Pathology, Royal Bournemouth Hospital, Bournemouth, UK; 3Medical Oncology Group, Institute of Cancer, St Bartholomew’s Hospital, London, UK; 4Clinical Trial Service Unit, University of Oxford, Oxford, UK; 5West Midlands Regional Genetics Laboratory, Birmingham Women’s Hospital, Birmingham, UK and 6The Genetic Epidemiology and Bioinformatics Research Group, Human Genetics Division, University of Southampton, Southampton, UK Historically, genes targeted by recurrent chromosomal One such example is deletion of the long arm of chromosome deletions have been identified within the smallest genomic 13, which is the most frequent alteration in chronic lymphocytic region shared in all patients, the minimally deleted region leukemia (CLL). Early G-banding demonstrated that 13q dele- (MDR). However, deletions this small do not occur in all patients 2 and are a simplification of the impact larger heterogeneous tions involved multiple non-overlapping chromosomal regions. deletions have during carcinogenesis. We use the example of Although it was initially suggested that RB1 was the pathogenic 13q14 deletions in chronic lymphocytic leukemia to show that locus,3 homozygous deletions at a more telomeric locus genes outside MDRs are associated with disease progression. were identified.3–5 Physical maps of this region also identified Genomic profiling of 224 patients identified 205 copy number several non-overlapping MDRs,6–8 implicating a multigenic alterations on chromosome 13 in 132 cases. Deletions including tumor suppressor mechanism. Ultimately, a 10 kb transcript-rich DLEU2 were heterogeneous (845 Kb–96.2 Mb) and identified two MDR including exons of two genes, DLEU1 and DLEU2, breakpoint cluster regions within short interspersed nuclear 9 elements proximal to DLEU2 and within long interspersed was identified. Sequence mutations and aberrant methylation nuclear elements/L1 repeats distal to GUCY1B2. After defining a patterns in this region have not been observed.10–12 The deletion class on the basis of size and location, we show that identification of the miR15a/16–1 microRNA cluster within (a) at diagnosis, larger deletions (class II) were associated with this region was a pivotal observation,13 and it is now clear that a significantly increased risk of disease progression (odds this cluster drives a lymphoproliferative phenotype in vivo.14 ratio ¼ 12.3; P ¼ 0.005), (b) in progressive patients, class II deletions were enriched (P ¼ 0.02) and (c) this association was Interestingly, only a fraction of miR15a/16–1 knock-out mice independent of IgVH mutational status, ZAP70 expression and developed B-cell malignancies, whereas the MDR-deleted mice ATM/TP53 deletion. Deletion of a 1 Mb gene cluster (48.2– exhibited more aggressive disease. This observation supports a 49.2 Mb), including SETDB2, PHF11 and RCBTB1, was signifi- multigenic hypothesis, and TRIM13 (DLEU5) and DLEU7 have cantly associated (Po0.01) with disease progression. Here, we been implicated, possibly through altered ubiquitination or show that the deletion of genes outside MDRs can influence NF-KB signaling.15,16 It has been proposed that 13q deletions clinical outcome. Leukemia (2011) 25, 489–497; doi:10.1038/leu.2010.288; could be categorized into two types; Type I deletions target published online 10 December 2010 a region including the MDR, whereas larger Type II deletions Keywords: SNP array; copy number alterations; 13q deletion; CLL; include the RB1 locus and were enriched in treated patients and disease progression those with higher Rai stage.17 The significance of large 13q deletions and RB1 in particular, is further emphasized by their association with elevated genome complexity.18 Introduction It is likely that the biological consequence of a unique deletion anatomy is complex, resulting in the disruption of Chromosomal deletions are recurrent features of human multiple regulatory sequences. Furthermore, this is likely to malignancy and can be critical events for the inactivation be the situation with 13q deletions in other tumor types, such of tumor suppressor genes in human cells. A plethora of genes as lymphoma, multiple myeloma and prostate cancer, as well have been identified in almost every tumor type through the as deletion events in cancer in general. Here, we employ identification and characterization of minimally deleted regions genomic profiling to show that 13q deletion size is associated (MDRs).1 Although MDRs have been critical ‘signposts’ to with disease progression. As a consequence, we propose a novel the location of cancer genes, they are a simplification of the gene cluster centromeric to the 13q MDR that may contribute to architecture and gene content of these deletions in patients. clinical outcome. Indeed, deletions are invariably larger, and multiple non- overlapping MDRs are often described. Materials and methods Correspondence: Dr JC Strefford, Cancer Genomics Group, Cancer Sciences Division, Somers Cancer research Building, Southampton Patients and molecular diagnostic assays General Hospital, Tremona Road, Southampton SO16 6YD, UK. A total of 224 CLL patients diagnosed on the basis of standard E-mail: [email protected] morphologic and immunophenotypic criteria were included in 7These authors contributed equally to this work 8These authors share senior authorship this study and sub-divided into three cohorts (Supplementary Received 18 August 2010; revised 13 October 2010; accepted 8 Table 1). Cohort I comprised 63 patients, where samples were November 2010; published online 10 December 2010 taken at disease presentation from patients with either stable 13q deletion size in CLL H Parker et al 490 disease for at least 5 years (n ¼ 38) or progressive disease within in the absence of paired normal DNA, copy number neutral 3 years (n ¼ 25). Cohort II consisted of 64 unselected patient loss-of-heterozygosity (CNNLOH) was as a region greater than samples taken at disease progression ranging from 0 to 22.5 20 Mb, extending to a telomere. years after diagnosis (median 2.3 years). Cohort III consisted of samples taken at enrollment to the UK CLL4 treatment trial19 from 97 patients treated on the fludarabine and cyclophos- Confirmation with array-based comparative genomic phamide arm, sub-divided on the basis of treatment response; hybridization with either complete (n ¼ 49), partial (n ¼ 40) or no response To confirm the SNP6.0. data, DNA samples from 22 patients (n ¼ 8) to treatment. Informed consent was obtained from all were also profiled using the Human Genome CGH Custom patients in accordance with the Helsinki declaration. Microarray (8 Â 60K, Agilent Technologies, Stockport, UK) Fluorescence in situ hybridization analysis was performed on according the manufacturer’s instructions. Test DNA samples all cases for the presence of established rearrangements using a were sex-matched with normal genomic reference DNA range of commercially available probes (Abbott Diagnostics, (Promega, Southampton, UK) and analysis was performed using Maidenhead, UK; DakoCytomation, Glostrup, Denmark) accor- proprietary software (DNA Analytics, Agilent Technologies). ding to the manufacturers’ instructions. Chromosomal analysis was performed and described according to the International System for Human Cytogenetic Nomenclature.20 ZAP70 and Statistical analysis CD38 expression was determined as previously described,21,22 Statistical analysis was performed using STATA (9.2) on a linux where 10 and 30% positive cells were classed as positive, platform. Logistic regression was employed within the indivi- respectively. IGHV genes were sequenced as previously dual cohorts for binary response variables. Variables examined described23 and a cut-off of X98% germ-line homology was included the disease progression variable (stable or progressive taken to define the unmutated sub-set (Supplementary Materials disease), presence/absence of 13q deletion and class I/II 13q & Methods and Supplementary Table 1). deletion category. Age at diagnosis and gender were included as covariates in all models where available (age at diagnosis was not available for cohort III). In cohorts I and II, overall survival Genomic profiling was defined as time, in months, from diagnosis to death or to the DNA extraction, SNP6.0. array hybridization and data last follow-up date for survivors. In cohort III, overall survival extraction. Genomic DNA was extracted from fluorescent- was defined as time from randomization, on entry, to the CLL4 activated cell sorter-purified CD19 þ lymphocytes, CD19À clinical trial, to death, or to the follow-up date for survivors. granulocytes and buccal swabs using standard approaches, Progression-free survival was only measured in cohort III and and the concentration and purity was assessed using gel was defined as time from randomization to relapse needing electrophoresis and spectrophotometry (NanoDrop ND-1000, further therapy, progression or death or to the follow-up date for Thermo Scientific, Wilmington, NC, USA). DNA was amplified, those with no progression/death. In all cohorts, time to first labeled
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