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, Jade Forster, Helen Parker, Anton Parker, Ana E Rodríguez, Tracy Chaplin, Anne Gardiner, Andrew J Steele, Andrew Collins, Bryan D Young, Anna Skowronska, Daniel Catovsky, Tatjana Stankovic, David G Oscier, Jonathan C Strefford

Research output: Contribution to journalArticlepeer-review

55 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)736-42
Number of pages7
JournalHaematologica
Volume99
Issue number4
DOIs
Publication statusPublished - Apr 2014

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Antineoplastic Combined Chemotherapy Protocols
  • Ataxia Telangiectasia Mutated Proteins
  • Chromosome Aberrations
  • Chromosomes, Human, Pair 11
  • Female
  • Gene Deletion
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Leukemia, Lymphocytic, Chronic, B-Cell
  • Male
  • Middle Aged
  • Mutation
  • Neoplasm Staging
  • Patient Outcome Assessment
  • Polymorphism, Single Nucleotide
  • Prognosis
  • Sequence Deletion

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