The Correlation Between Deletion Architecture, ATM Mutational Status and BIRC3 Disruption in 11q-Deleted CLL
Authors: Rose-Zerilli Matthew JJ , Forster Jade , Parker Helen , Parker Anton , Rodríguez Ana E , Chaplin Tracy , Gardiner Anne , Collins Andrew , Young Bryan D , Stankovic Tatjana , Oscier David , Strefford Jonathan C. 
Published: October 2019

Abstract
Abstract 658
In CLL, 11q23 deletion (encompassing the ATM gene) predicts a poor response to initial treatment with DNA damaging agents that can be ameliorated by the addition of anti-CD20 antibodies. 30–40% of 11q-deleted CLL cases have an inactivating ATM mutation on the remaining allele. In the UK CLL4 trial, bi-allelic ATM abnormalities were associated with a shorter PFS than those with mono-allelic ATM loss. The additional observation of a shorter PFS in cases with mono-allelic ATM loss compared to those with an ATM mutation in the absence of an 11q deletion suggests a potential pathogenic role for other genes within the 11q deleted region. A recent study provides evidence that loss and/or mutation of BIRC3, located at 11q22, that encodes a negative regulator of non-canonical NFkB signalling, may be an independent marker of poor outcome in CLL. In order to provide more data on the relative frequency and clinical significance of ATM and BIRC3 loss and mutation, we have screened a cohort of previously untreated patients (n=264) enriched for cases with an 11q23 deletion detected by FISH (n=80) using SNP6.0 profiling (n = 264) and HRM-PCR/DHPLC & sequencing of the ATM (all exons; n=130), and BIRC3 (mutation hotspots: exons 5,7,10; n=258) genes. SNP6.0 copy number analysis identified 112 deletions on chromosome 11 in 76 cases, of which 69 had deletions including ATM (27.8Mb; 521kb–58Mb). Although a 416Kb Minimally Deleted Region (MDR) was defined (107.5–107.9Mb; hg18) containing 6 genes including ATM, in only 4% of 11q-deleted cases was a deletion confined to the MDR and invariably 11q23 deletions were much larger. The entire BIRC3 gene was only deleted in cases with ATM loss, and always within a single deletion event encompassing both genes. BIRC3 was deleted in 57 11q-deleted cases (83%) and in 4 cases (6%) the proximal deletion breakpoint resulted in partial deletion of BIRC3 that is predicted to cause protein truncation by removal of the RING domain. Additional deletion events not including ATM were identified in our series, but none of these encompassed BIRC3. In ATM deleted and non-deleted cases, the frequency of an ATM mutation of the retained allele was 38 and 21% respectively. In 11q-deleted cases with a wild-type ATM allele, three harboured both a deletion and mutation of BIRC3 (5% of BIRC3-deleted CLL). Mutations were located in either the CARD (frameshift mutation) or RING domains (STOP codon point mutation & 3bp indel) of the protein, and two are predicted to eliminate the C-terminal RING domain responsible for proteasomal degradation of MAP3K14. These three cases were also positive for trisomy 12, lacked an ATM mutation or TP53 abnormality, and two had mutations within the PEST domain of NOTCH1. Patients with deletion and mutation of BIRC3 were all treated (FC or F) within 39 months (mean TFS = 16 mths; range: 1–39mths) from diagnosis and after 9 years of follow up only one patient survived (mean OS = 83 mths). In conclusion, given the concordance between ATM and BIRC3 loss, and the low incidence of BIRC3 mutations, much larger studies would be required to evaluate whether disruption of BIRC3 has independent prognostic significance in an untreated cohort.

Disclosures:
No relevant conflicts of interest to declare.