title: 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.
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.
authors.affiliation: JCS@soton.ac.uk.
authors.forename: Matthew J J
authors.initials: MJ
authors.lastname: Rose-Zerilli
authors.forename: Jade
authors.initials: J
authors.lastname: Forster
authors.forename: Helen
authors.initials: H
authors.lastname: Parker
authors.forename: Anton
authors.initials: A
authors.lastname: Parker
authors.forename: Ana E
authors.initials: AE
authors.lastname: Rodríguez
authors.forename: Tracy
authors.initials: T
authors.lastname: Chaplin
authors.forename: Anne
authors.initials: A
authors.lastname: Gardiner
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Steele
authors.forename: Andrew
authors.initials: A
authors.lastname: Collins
authors.forename: Bryan D
authors.initials: BD
authors.lastname: Young
authors.forename: Anna
authors.initials: A
authors.lastname: Skowronska
authors.forename: Daniel
authors.initials: D
authors.lastname: Catovsky
authors.forename: Tatjana
authors.initials: T
authors.lastname: Stankovic
authors.forename: David G
authors.initials: DG
authors.lastname: Oscier
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Strefford
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D002869:Chromosome Aberrations; D002880:Chromosomes, Human, Pair 11; D005260:Female; D017353:Gene Deletion; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D063868:Patient Outcome Assessment; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases
chemical_list: D051034:Inhibitor of Apoptosis Proteins; C494832:BIRC3 protein, human; D000075747:Baculoviral IAP Repeat-Containing 3 Protein; D044767:Ubiquitin-Protein Ligases; D064007:Ataxia Telangiectasia Mutated Proteins