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© Ferrata Storti Foundation ARTICLES Chronic Lymphocytic Leukemia ATM mutation rather than BIRC3 deletion and/or mutation predicts reduced survival in 11q-deleted chronic lymphocytic leukemia: data from the UK LRF CLL4 trial Matthew J.J. Rose-Zerilli,1 Jade Forster,1 Helen Parker,1 Anton Parker,2 Ana E. Rodri guez,3 Tracy Chaplin,4 Anne Gardiner,2 Andrew J. Steele,1 Andrew Collins,5 Bryan D. Young,4 Anna Skowronska,́ 6 Daniel Catovsky,7 Tatjana Stankovic,6 David G. Oscier,1,2 and Jonathan C. Strefford1 1Cancer Sciences, Faculty of Medicine, University of Southampton, Southampton, UK; 2Department of Haematology, Royal Bournemouth Hospital, Bournemouth, UK; 3Cancer Research Center (IBMCC-CSIC), University of Salamanca, Spain; 4Centre for Medical Oncology, Barts and The London School of Medicine and Dentistry, London, UK; 5Human Development and Health, Faculty of Medicine, University of Southampton, UK; 6School of Cancer Sciences, University of Birmingham, UK; and 7Haemato-oncology Research Unit, Division of Molecular Pathology, The Institute for Cancer Research, Sutton, UK ABSTRACT ATM mutation and BIRC3 deletion and/or mutation have independently been shown to have prognostic signifi- cance in chronic lymphocytic leukemia. However, the relative clinical importance of these abnormalities in patients with a deletion of 11q encompassing the ATM gene has not been established. We screened a cohort of 166 patients enriched for 11q-deletions for ATM mutations and BIRC3 deletion and mutation and determined the overall and progression-free survival among the 133 of these cases treated within the UK LRF CLL4 trial. SNP6.0 profiling demonstrated that BIRC3 deletion occurred in 83% of 11q-deleted cases and always co-existed with ATM deletion. For the first time we have demonstrated that 40% of BIRC3-deleted cases have concomitant deletion and mutation of ATM. While BIRC3 mutations were rare, they exclusively occurred with BIRC3 deletion and a wild- type residual ATM allele. In 11q-deleted cases, we confirmed that ATM mutation was associated with a reduced overall and progression-free survival comparable to that seen with TP53 abnormalities, whereas BIRC3 deletion and/or mutation had no impact on overall and progression-free survival. In conclusion, in 11q-deleted patients treated with first-line chemotherapy, ATM mutation rather than BIRC3 deletion and/or mutation identifies a sub- group with a poorer outcome. Foundation Introduction and 3) patients in the UK LRF CLL4 trial with biallelic ATM Stortiabnormalities (deletion and mutation) have a poorer outcome Deletion of chromosome 11q (termed del11q) was first rec- following the initial therapy with alkylating agent and/or ognized as a recurrent karyotypic abnormality acquired dur- purine analog therapy compared to those with mono-allelic ing the course of the disease in patients with progressive ATM deletion or mutation.20 chronic lymphocytic leukemia (CLL).1 Subsequent interphase However, uncertainty remains as to whether the poorer fluorescence in situ hybridization (FISH) analysis identified outcome of patients with 11q deletion in the absence of an 11q deletion in approximately 20% of patients with CLL, and ATM mutation is simply a consequence of ATM haploinsuffi- associations with bulky lymphadenopathy and a poorer out- ciency. Alternative possibilities that have been considered come for patients under the age ofFerrata 55 years were noted. 2,3 include deletion, mutation or epigenetic silencing of other Subsequent studies have documented associations with genes either within or outside the MDR or the associated unmutated IGHV genes, del13q,© genomic complexity, short genomic complexity.8,21–23 Neither candidate gene sequencing telomeres, progressive disease and a poor outcome in nor whole exome sequencing studies have identified muta- response to alkylating agent or purine analog treatment, tions within other genes located in the MDR.24,25 However, which was improved by their use in combination and amelio- recent data have revealed a high incidence of deletion or, rated by the further addition of rituximab.4–10 more rarely, mutation of BIRC3, a negative regulator of non- Genomic profiling studies have refined previous karyotypic canonical NFκB signaling located at 11q22. It has been report- and FISH studies showing that 11q deletions are mono-allelic, ed that BIRC3 deletion and/or mutation (previously termed frequently large and include a minimally deleted region “BIRC3 disruption”) occurs in a mutually exclusive manner (MDR), which encompasses the ATM gene.11–14 Evidence that with TP53 abnormalities, is associated with fludarabine-resis- ATM is a key target of 11q deletions is derived from findings tance,26 and when detected at diagnosis predicts for poor that: 1) mutation of the ATM gene is found in 30-40% of overall survival independent of 11q deletion.27 patients with an 11q deletion;15,16 2) the presence of an ATM The above data strongly suggest that there are subsets of mutation results in impaired DNA damage responses;15,17–19 del11q patients that exhibit differing responses to standard ©2014 Ferrata Storti Foundation. This is an open-access paper. doi:10.3324/haematol.2013.098574 The online version of this article has a Supplementary Appendix. Manuscript received on September 27, 2013. Manuscript accepted on December 23, 2013. Correspondence: [email protected] 736 haematologica | 2014; 99(4) 11q23 deletions, ATM and BIRC3 mutations in CLL treatment. However, the relative frequency and clinical made. An additional 33 11q-deleted patients were also included to significance of ATM and BIRC3 abnormalities is unclear. allow more significant associations between the 11q deletion and This study addresses this issue in a large cohort of 11q- other genomic variables to be made, such as with mutational sta- deleted patients detected by SNP6 profiling and screened tus of ATM and BIRC3. The additional del11q patients were sam- for ATM and BIRC3 mutations. As a consequence, in the pled subsequent to the development of progressive disease, with a context of a phase III clinical trial of chemotherapy, we median time from diagnosis of 3.2±5.2 years (±1 standard devia- show that ATM mutational status remains the most clini- tion (SD); range 1 month-27 years). For the entire cohort of 166 cally informative genomic lesion in 11q-deleted CLL, iden- patients, mutational data were available for TP53 (n=125), SF3B1 tifying cases with outcome comparable to TP53 deletion (n=140) and NOTCH1 (n=146).28,29 Details on the molecular diag- and/or mutation patients, and that the presence of BIRC3 nostic assays30,31 are available in the Online Supplementary Methods. deletion and/or mutation is associated with outcome com- Informed consent was obtained from all patients in accordance parable to other 11q-deleted CLL cases. with the Declaration of Helsinki and our local ethics committee gave their approval for the study. Methods DNA extraction, SNP6 array hybridization, Patients and molecular diagnostic assays data extraction and analysis A total of 166 untreated CLL patients diagnosed according to Genomic DNA was extracted from CLL B cells (n=166) and buc- standard morphological and immunophenotypic criteria were cal swabs (n=32), prior to being purified, amplified, labeled and included in this study (Table 1 and Online Supplementary Table S1). hybridized to the Affymetrix SNP6.0 platform (Affymetrix, Santa This cohort principally included patients from the UK LRF CLL4 Clara, CA, USA) as previously described32 (Online Supplementary trial9 (n=133) which allowed accurate clinical correlations to be Methods). Table 1. Cohort characteristics. Characteristics Sub-groups All Cases (%) CLL4 Cases n (%)2 non-del(11q) del(11q) Number of cases 166 (100) 97 (73) 36 (27) Gender Male 124 (75) 71 (73) 27 (75) Female 42 (25) 26 (27) 9 (25) Age at diagnosis Mean 63 Foundation71 62 Range 39-89 56-86 44-80 Binet stage at diagnosis or randomization A 48 (31) 23 (24) 7 (19) B 69 (44) 47 (49) 18 (50) C 40 (25) 27 (28) 11 (31) Trisomy 12 by SNP6 Trisomy 13 (8) 9 (9) 3 (8) Normal Storti 153 (92) 88 (91) 33 (92) 13q by SNP6 Deleted 94 (66) 51 (53) 22 (61) Normal 72 (44) 46 (47) 14 (39) 17p by SNP6 Deleted 12 (7) 9 (9) 1 (3) Normal 154 (93) 88 (91) 35 (97) IGHV mutation statusa Unmutated 98 (68) 56 (64) 30 (83)1 Mutated 47 (32) 32 (36) 6 (17) CD38 positivityb Ferrata + 68 (50) 32 (42) 18 (55) - 69 (50) 44 (58) 15 (45) ZAP70 positivityc © + 74 (54) 42 (51) 21 (64) - 63 (46) 40 (49) 12 (36) ATM mutation statusd T-Mutated 17 (16) 5 (10) 10 (32)3 NT-Mutated 19 (18) 8 (17) 4 (13)4 Unmutated 69 (66) 35 (73) 17 (55) TP53 mutation statuse Mutated 9 (7) 7 (8) 2 (6) Unmutated 116 (93) 76 (92) 30 (94) BIRC3 deletion status Deleted 57 (34) 0 (0) 32 (89) Normal 109 (66) 97 (100) 4 (11) BIRC3 mutation status Mutated 3 (2) 0 (0) 2 (6) Unmutated 159 (98) 95 (100) 34 (94) NOTCH1 mutation statusf Mutated 14 (10) 10 (12) 2 (6) Unmutated 132 (90) 75 (88) 32 (94) SF3B1 mutation statusg Mutated 28 (20) 19 (24) 3 (9) Unmutated 112 (80) 61 (76) 29 (91) A proportion of cases were not screened for our panel of molecular and cytogenetic biomarkers; not screened= 21 a, 29 b, 29 c, 61 d, 41 e, 20 f, 26 g. 1A significant positive association 2 2 was identified between the presence of del11q and an unmutated IGHV sequences in the CLL4 cases (P=0.03, 2x2 χ test). The columns for del11q and non-del11q are based on the SNP6.0 profiling data. 3A significant positive association was identified between the frequency of truncating ATM mutations (T-Mutated) and presence of del11q. (P=0.02, 2x2 2 4 2 χ test). The frequency of non-truncating ATM mutations (NT-Mutated) was similar in non-del11q and del11q cases.
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