Abstract 3004: Comparison of somatic alterations in the genome and transcriptome of 1,705 pediatric leukemia and solid tumors: a report from the Children’s Oncology Group (COG) - NCI TARGET Project

To discover common and sub-type specific somatic alterations affecting key biological processes in pediatric cancers, we analyzed point mutations, copy number alterations, gene fusions and structural alterations detected from paired tumor-normal whole genome sequencing (n=655), whole exome sequencing (n=1,108), and RNA-seq data (n=913) of 1,705 leukemia and solid tumors. Our cohort consists of 693 B-lineage Acute Lymphoblastic Leukemia (B-ALL), 264 T-ALL, 211 Acute Myeloid Leukemia (AML), 318 Neuroblastoma (NBL), 128 Wilms Tumor (WT), and 91 Osteosarcoma (OS) with a median mutation rate of 0.28-0.58 per Mb. We identified 130 potential driver genes based on significance of variant recurrence and pathogenicity within each cancer type and across all cancer types. Seventy-two (55%) driver genes were significant in one cancer type, thirty eight were significant in > 1 leukemia subtype, thirteen (NRAS, WT1, MYCN, PTEN, TP53, KRAS, RB1, ATRX, PTPN11, MLLT1, BCOR, SETD2, NF1) were significant in both leukemia and solid tumor while the remaining seven (MGA, SF3B1, ASXL1, BCORL1, STAG2, ACTB, NIPBL) were significant only in pan-cancer analysis. The number of mutated driver genes per sample ranged from 0.8 in WT to 5.8 in T-ALL, lower when considering only point mutations (from 0.3 in NBL to 3.1 in T-ALL). The most frequently mutated biological processes affecting both leukemia and solid tumor were transcription factors (56% of samples), cell cycle (41%), epigenetic regulators (36%), Ras signaling (21%), PI-3K (11%), and the MYC complex (7%). By contrast, the JAK signaling pathway was mutated only in leukemia (16%) while mutations in the NOTCH signaling pathway were exclusive to T-ALL (77%). Aberrant transcription may also affect the normal function of a driver gene. For example, the RAS signaling pathway was mutated in B-ALL (35%), T-ALL (15%), AML (37%) and NBL (4.3%). Aside from the known KRAS 4a isoform found in all cancer types, we discovered two novel KRAS isoforms present in 71.1% of B-ALL, 67.9% of T-ALL, 71.3% of AML and 3.0% of NBL but not in WT or OS. Allele-specific expression (ASE) was detected in 205 (6.8%) of 3,016 expressed somatic mutations, and 97% (32 out of 33) of truncation mutations on autosomes exhibit reduced expression of the mutant allele likely due to nonsense mediated decay. Two ASE mutations, WT1 D447N in a cytogenetically normal AML and JAK2 D873N in a B-ALL, were selected for single-cell sequencing and successfully validated. Only 44% of our driver genes match those identified in adult cancer. This, coupled with our finding that point mutations only accounted for 48% of the driver alterations, may provide new insight into the design of precision treatment for pediatric cancer. Our presented data will be made public at NCI’s Genome Data Commons (gdc.cancer.gov) and can be explored on our ProteinPaint data portal (pecan.stjude.org). Citation Format: Xiaotu Ma, Yu Liu, Yanling Liu, Michael Edmonson, Charles Gawad, Xin Zhou, Yongjin Li, Michael Rusch, John Easton, Mark Wilkinson, Leandro C. Hermida, Sean Davis, Malcolm Smith, Jaime Guidry Auvil, Paul Meltzer, Ching C. Lau, Elizabeth Perlman, John M. Maris, Soheil Meshinchi, Stephen P. Hunger, Daniela S. Gerhard, Jinghui Zhang. Comparison of somatic alterations in the genome and transcriptome of 1,705 pediatric leukemia and solid tumors: a report from the Children’s Oncology Group (COG) - NCI TARGET Project [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 3004. doi:10.1158/1538-7445.AM2017-3004