Introduction: Prognostic biomarkers in childhood acute lymphoblastic leukemia (ALL) are vital for risk-stratification and intensifying therapy for children at high risk for remission induction failure or relapse. Copy number alterations in genes such as IKZF1 and VPREB1 have been shown to correlate with poor outcome in ALL, highlighting genetic alterations as prognostic markers (NEJM 360:470, 2009, Leukemia 28(1):216-20, 2014). A second focal deletion in chromosome 22q11.22, 200 kilobases (Kb) in length, occurs more frequently and in the same IGLL region as VPREB1 and is distinct from deletions associated with physiologic IGLL rearrangement. We further investigated this novel genomic lesion, 22q11.22, and the prevalence of co-occurrence with IKZF1.
Methods: 22q11.22 deletions were characterized in a compiled childhood ALL cohort (N=832) and correlated with available clinical outcome using multiple previously published studies (Clinical outcome total N=730; Utah Cohort [N=56], TARGET P9906 cohort [N=215], St. Jude Children's Research Hospital cohort [SJCRH, N=236], Children’s Hospital of Philadelphia cohort [CHOP, N=160], and Down Syndrome cohort [DS, N=63]). Microarray data was analyzed (Utah = Molecular Inversion Probe 330K [Affymetrix]; TARGET = SNP 500K [Affymetrix]; SJCRH = SNP 500K/6.0 [Affymetrix], CHOP = 850K, 610K, and Omni Quadv1 [Illumina], DS = SNP 500K, MIP 330K [Affymetrix]) by Nexus Copy Number (BioDiscovery, Inc.).
Results: ALL patients that harbored copy number deletion 22q11.22 were present in about 30-45% of each cohort: Utah = 42.8%, TARGET = 29%, SJCRH = 40%, CHOP = 34%, DS = 46.7%. The majority of deletions, 93%, had a common recurring region just under 12 Kb in length. The 12 Kb deleted segment encodes no known genes. Patients that harbored a combined deletion in both IKZF1 and 22q11.22 (IKZF1+22q) were present in about 10-15% of each cohort: Utah = 12.5%, TARGET = 18%, SJCRH = 8.4%, CHOP = 6.3%, DS = 14.4%. IKZF1+22q conferred worse event-free survival (N=730, P=0.0062) compared to those with only IKZF1 deletions and worse overall survival (N=507, P=0.0365). Additionally, those patients with IKZF1+22q losses had a median decrease in event-free survival compared to those patients with neither deletion (normal cases): TARGET (high risk cohort) = 0.63 years, P=<0.0001, SJCRH (standard, low risk cohort) = 10 years, P=<0.0001, DS = 2.3 years, P=<0.0001.
Conclusion: We present further evidence that non-physiological deletions within the IGLL locus is associated with worse outcome in pediatric ALL and combined with IKZF1, these double deletions identify a population of patients with very poor outcomes. These combined alterations may be useful to identify patients in the future for high risk stratification and further work is now needed to understand the mechanism and biological consequence of this common loss at 22q11.22 in childhood ALL.
Citation Format: Julia A. Meyer, Clint C. Mason, Luke Maese, Deqing Pei, Cheng Cheng, Ching-Hon Pui, Mel Greaves, Richard Aplenc, Charles G. Mulligan, Elizabeth Raetz, Rodney R. Miles, Karen R. Rabin, Joshua D. Schiffman. Focal 22q11.22 deletions combined with IKZF1 alterations are associated with worse clinical outcome in acute lymphoblastic leukemia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4884. doi:10.1158/1538-7445.AM2017-4884