IKZF1 and 22q11.22 Deletions and PDGFRA Gains Are Associated with Poor Outcome in Down Syndrome Acute Lymphoblastic Leukemia

• Published in: Blood 2012-11, Vol.120 (21), p.289-289
• Main Authors: Rabin, Karen R, Mason, Clinton C, Gurusiddappa, Sivashankarappa, Leung, Hon-Chiu Eastwood, Morrison, Debra J., Bhojwani, Deepa, Barnette, Phillip, South, Sarah T., Miles, Rodney R., Devidas, Meenakshi, Pession, Andrea, Basso, Giuseppe, Potter, Nicola E, Kearney, Lyndal, Moorman, Anthony V., Raimondi, Susana C., Jeha, Sima, Pui, Ching-Hon, Carroll, William L., Loh, Mignon L., Hunger, Stephen P., Mullighan, Charles G, Schiffman, Joshua D.
• Format: Article
• Language: English
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.V120.21.289.289

Abstract 289▪▪This icon denotes a clinically relevant abstract Children with Down syndrome (DS) have an increased risk of developing acute lymphoblastic leukemia (ALL), and consistently demonstrate poorer outcomes due to higher rates of both relapse and treatment-related mortality compared to other children with ALL. The biology of ALL in DS is unique, with lower frequency of the classic cytogenetic lesions generally observed in childhood ALL, and increased frequency of JAK2 mutations and CRLF2 rearrangements, which are not clearly associated with adverse prognosis in DS-ALL. In order to improve risk stratification and identify potential novel therapeutic targets in this vulnerable population, we analyzed 90 DS-ALL cases for prognostically significant copy number abnormalities (CNAs) in a collaborative cohort from the Children’s Oncology Group (n=30), St. Jude Children’s Research Hospital (n=22), AIEOP (n=16), Texas Children’s Cancer Center (n=10), UKALL 2003 (n=6) and an archival UK sample (n=1), and Utah’s Primary Children’s Medical Center (n=5). Copy number profiling was performed using 500K, 6.0, CytoScan HD, and OncoScan FFPE Express arrays (Affymetrix), and Human CNV370-Duo arrays (Illumina). Gene expression profiling was performed using U133 Plus2.0 arrays (Affymetrix). Copy number was analyzed with Nexus Copy Number (BioDiscovery, Inc.) and gene expression was analyzed with Partek Genomics Suite (Partek, Inc.) and Gene Set Enrichment Analysis (Broad Institute). Deletions of a focal region on 22q11.22 (present in 28.9% of cases, similar to the incidence previously reported in a non-DS cohort [Mangum et al, ASH 2011:741]), and deletions of IKZF1 (present in 20.0% of cases), were significantly associated with poor event-free survival (EFS) (5-year EFS was 88.6 ± 6.3% in wild-type cases [n=31], 68.1 ± 13.3% in cases with deletion of 22q11.22 only [n=15], and 60.0 ± 21.9% in those with deletion of IKZF1 only [n=5]; combined deletion [n=6] was associated with an even poorer EFS (33.3 ± 19.3%, p