Abstract 4755: Genome wide analysis of hypodiploid acute lymphoblastic leukemia identifies a high frequency of mutations targeting the IKAROS gene family and Ras signaling
Authors: Holmfeldt Linda , Zhang Jinghui , Payne-Turner Debbie , Ma Jing , Devidas Meenakshi , Carroll Andrew J. , Heerema Nyla A. , Gastier-Foster Julie M. , Raimondi Susana C. , Loh Mignon L. , Hunger Stephen , Mullighan Charles G. 
Published: June 2012

Abstract
Hypodiploid acute lymphoblastic leukemia (ALL) comprises up to 7% of pediatric ALL cases and is characterized by chromosomal loss and very poor outcome. Prognosis is associated with the severity of aneuploidy, with the worst outcome for cases with less than 32 chromosomes. To gain insights into the genetic basis of hypodiploid ALL, we performed a genome wide analysis of genetic alterations in 128 hypodiploid childhood ALL cases treated by the Children's Oncology Group and St Jude. This cohort comprised 51 near haploid cases (24-31 chr), 24 low hypodiploid cases (32-39 chr), 29 masked hypodiploid cases (with a doubled near haploid or low hypodiploid genome), 2 high hypodiploid cases (40-43 chr) and 22 cases with 44-45 chromosomes, the majority of which had a dicentric chromosome. DNA copy number alterations and loss of heterozygosity were examined using Affymetrix SNP 6.0 arrays, and candidate gene resequencing was performed for genes and pathways recurrently altered in ALL. We identified multiple recurring focal deletions, the nature and frequency of which were associated with degree of aneuploidy. The most common alteration was deletion of CDKN2A/B (encoding INK4/ARF) in hypodiploid ALL cases with 40-45 chromosomes (75% of cases) compared to 23% in the other hypodiploid ALL subgroups. The B-lymphoid transcription factor gene PAX5 was mutated more frequently in dicentric cases (59%) than in cases with less than 44 chromosomes (7%). We also observed recurring deletions in the histone loci at 6p22 and PAG1 (11% and 10%, respectively, of near haploid, low and masked hypodiploid cases). A striking novel finding was a high frequency of alterations targeting the IKAROS family members IKZF2 (encoding the lymphoid transcription factor HELIOS) and IKZF3 (AIOLOS) that only were present in near haploid, low and masked hypodiploid cases (IKZF2 21%; IKZF3 10%). Deletions of these genes are rare in other ALL subtypes. Conversely, alteration of IKZF1 (encoding IKAROS), found in up to 30% of non-hypodiploid ALL cases, was rare in hypodiploid ALL. Further, a high frequency of deletions and sequence mutations targeting the Ras signaling pathway (KRAS, NRAS, NF1, PTPN11 and FLT3) was observed in 45% of near haploid, low and masked hypodiploid ALL cases. Notably, the alterations of NF1 and IKZF2/3 were almost always mutually exclusive and mostly occurred in conjunction with loss of the other copy of the corresponding chromosome, resulting in biallelic deletion and/or inactivation of the involved gene. This study provides the first detailed genetic analysis of this high risk ALL subtype, and suggests that genetic alterations targeting Ras signaling and lymphoid development are central to the pathogenesis and poor prognosis of hypodiploid ALL. Moreover, these results suggest that therapeutic targeting of Ras signaling may be of clinical benefit in this very high risk ALL subtype.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4755. doi:10.1158/1538-7445.AM2011-4755