Abstract 4870: Integrated genomic analysis of hypodiploid acute lymphoblastic leukemia
Authors: Holmfeldt Linda , Diaz-Flores Ernesto , Zhang Jinghui , Payne-Turner Debbie , Andersson Anna , Chen Shann-Ching , Becksfort Jared , Ma Jing , Wei Lei , Easton John , Pei Deqing , Cheng Cheng , Pui Ching-Hon , Devidas Meenakshi , Carroll Andrew J. , Heerema Nyla A. , Gastier-Foster Julie M. , Raimondi Susana C. , Mardis Elaine R. , Wilson Richard K. , Downing James R. , Hunger Stephen P. , Loh Mignon L. , Mullighan Charles G. 
Published: August 2012

Abstract
Hypodiploid acute lymphoblastic leukemia (ALL) is an aggressive form of leukemia characterized by multiple whole chromosomal losses and very dismal outcome. Our previous genome wide study of hypodiploid childhood ALL cases treated by the Children's Oncology Group and St Jude, employed interrogation of DNA copy number alterations using Affymetrix SNP 6.0 microarrays, candidate gene resequencing and gene expression profiling using Affymetrix U133 Plus 2.0 microarrays. These analyses showed that this disease can be divided into multiple subtypes characterized by variation in the degree of aneuploidy, distinct submicroscopic deletions, sequence mutations and gene expression profile. Near haploid ALL (24-31 chromosomes) frequently harbors alterations of genes regulating Ras signaling (67.6%; NF1, NRAS, KRAS, PTPN11, FLT3, and PAG1), IKZF3 (encoding the lymphoid transcription factor AIOLOS; 13.2%), and a histone gene cluster at 6p22 (17.6%), while low hypodiploid ALL (32-39 chromosomes) is enriched for IKZF2 (HELIOS; 52.9%), TP53 (70.6%) and RB1 (41.2%) alterations. A striking finding was exclusivity of Ras signaling and IKZF2/3 alterations, and biochemical indications of Ras pathway activation in both near haploid and low hypodiploid ALL. To further interrogate the genomic changes of hypodiploid ALL, we performed next generation sequencing using either Illumina GAIIx or HiSeq3000 sequencers on both tumor and matched remission DNA. Whole genome sequencing to at least 30 fold haploid coverage was performed on 10 near haploid and 8 low hypodiploid cases, and whole exome sequencing (Agilent SureSelect Human All Exon 50Mb) on 5 near haploid and 1 low hypodiploid cases. The burden of single nucleotide variations (SNVs) and insertion/deletion (indel) mutations was in general low in this ALL subtype, with 0-5 indels and 9-95 SNVs in coding regions and untranslated leader regions in the whole genome sequenced cases, where the majority of cases had fewer than 30 SNVs. Further, the number of structural variations, including the ones too small to be identified by SNP microarray analysis, and structural rearrangements, were also low, with less than 25 structural variations identified in the whole genome sequenced cases. For the whole exomes, between 10 and 42 non-silent SNVs and 1-2 indels were identified per case. No recurrent alterations not previously identified in the hypodiploid cohort were found in these 24 cases, indicating that the initial genome wide study of this cohort identified the major recurrent alterations in hypodiploid ALL. However, the recurrence screening including the remaining 78 near haploid and low hypodiploid cases in our cohort on the alterations identified by the whole genome and exome sequencing study is ongoing. Altogether, these findings provide critical new insights into the genetic basis of hypodiploid ALL, and indicate that therapeutic targeting of the Ras pathway should be pursued in this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4870. doi:1538-7445.AM2012-4870