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

• Published in: Haematologica (Roma) Vol. 99; no. 4; pp. 736 - 742
• Main Authors: Rose-Zerilli, M. J. J., Forster, J., Parker, H., Parker, A., Rodriguez, A. E., Chaplin, T., Gardiner, A., Steele, A. J., Collins, A., Young, B. D., Skowronska, A., Catovsky, D., Stankovic, T., Oscier, D. G., Strefford, J. C.
• Format: Journal Article
• Language: English
• Published: Italy Ferrata Storti Foundation 01.04.2014
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Ataxia Telangiectasia Mutated Proteins - genetics; Baculoviral IAP Repeat-Containing 3 Protein; Chromosome Aberrations; Chromosomes, Human, Pair 11; Female; Gene Deletion; Humans; Inhibitor of Apoptosis Proteins - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - diagnosis; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Leukemia, Lymphocytic, Chronic, B-Cell - genetics; Leukemia, Lymphocytic, Chronic, B-Cell - mortality; Male; Middle Aged; Mutation; Neoplasm Staging; Patient Outcome Assessment; Polymorphism, Single Nucleotide; Prognosis; Sequence Deletion; Ubiquitin-Protein Ligases
• ISSN: 0390-6078; 1592-8721; 1592-8721
• DOI: 10.3324/haematol.2013.098574

ATM mutation and BIRC3 deletion and/or mutation have independently been shown to have prognostic significance 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 subgroup with a poorer outcome.