Abstract 2075: Whole genome sequence analysis informs precision medicine of pediatric cancers

Several recent studies (including BASIC3, iCAT, INFORM, PEDS-MIONCOSEQ) have used whole exome sequencing (WES) and RNA-seq in order to identify targetable chromosomal alterations in a large variety of pediatric cancers. Few studies have attempted to evaluate whether a more comprehensive approach including WGS and RNA-seq could be used to identify novel events relevant to the pathogenesis of advanced pediatric cancer. We analyzed a total of 59 patients (37 solid tumors, 11 brain tumors, and 10 leukemia/lymphomas) to determine the feasibility of using whole-genome sequencing (WGS) technology in conjunction with RNA-seq in order to identify actionable/druggable alterations in the pediatric cancer genomes. WGS analysis has been performed on 75 samples, that were collected from 45 patients, either at diagnosis or at relapse. For WGS analysis of germline-tumor pairs, after performing the sequence alignment with BWA-MEM to gender-specific hg38 genomes, we have used and verified a set of computational methods: 1) MuTect2 for SNV calling, 2) cn.mops for CNV calling, 3) DELLY and LUMPY for SV calling. Here we present our findings on the sets of SNV, CNV, SV, and gene fusions that we have identified by WGSA and RNA-seq, respectively, with a particular emphasis on the druggable alterations, and on the tumor response in the murine PDX models of the pediatric cancers. Consistent with previous observations, the mutational burden across pediatric cancers was low. While common mutations were identified, there was a long-tail of mutations that occurred at a low frequency. As anticipated, samples obtained post-chemotherapy had a higher mutational burden than treatment naive samples. TP53 was the most commonly mutated gene, but we also identified SNVs in other genes commonly mutated in cancer, such as ASXL1, NOTCH2, and RB1. Other novel recurring variants were discovered, further analysis of which is ongoing. Our results indicate that integrated WGS and RNA-seq analysis is feasible in the clinical setting and can reliably identify variants reported on commercially available gene panel testing. However, this approach also resulted in additional clinically relevant findings and allows for novel discovery that will further advance our understanding of these rare and highly aggressive pediatric malignancies. Citation Format: Bogdan Tanasa, Alex Lee, Marcus Breese, Avanthi Shah, Stan Leung, Heng-Yi Liu, Aviv Spillinger, Kimberly Hazard, Arun Rangaswami, Sheri Spunt, Norm Lacayo, Tabitha Cooney, Eric Alejandro Sweet-Cordero. Whole genome sequence analysis informs precision medicine of pediatric cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2075.