Abstract 1287: Exploring somatic DNA structural alteration and aberrant genomic interactions in cancer through GenomePaint

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Abstract Somatic structural variations (SV) play an important role in tumorigenesis as they may cause oncogenic gene fusions or transcriptional activation of oncogenes by introducing aberrant promoter-enhancer interactions. Evaluating the oncogenic implications of SVs is challenging, especially for SVs in noncoding regions, which requires integrating data from 1) whole-genome sequencing (WGS), 2) RNA-seq from the tumor sample and series patient samples with same tumor type to compare with, 3) epigenetic profiling (ChIP-seq), and 4) genome-wide chromosome conformation capture studies such as Hi-C. To facilitate the discovery of oncogenic SVs, we developed GenomePaint, an interactive browser to integrate and visualize somatic SVs and copy number alterations (CNAs) analyzed by WGS, and gene expression data analyzed by RNA-seq in >2,000 pediatric cancers, as well as ChIP-seq and Hi-C data from pediatric tumors and cell lines. The genomic profiling of patient samples was generated by the St Jude/Washington University Pediatric Cancer Genome Project and the NCI-TARGET project, and includes all major subtypes of pediatric leukemia, solid tumors and brain tumors. A global view of the entire patient cohort using GenomePaint revealed SV hotspots (e.g. within first intron of TP53 in osterosarcoma) and recurrent CNAs (e.g. TAL1 deletion in T-ALL) in each cancer type. Each SV was integrated with results on gene expression, ChIP-seq and Hi-C, on the rearranged chromosome. Our discovery of the mechanism underlying aberrant MYC overexpression, in a subset of neuroblastomas (NBL) lacking MYCN amplification, proves the power of this tool in facilitating the discovery of oncogenic SV drivers. The sample with the highest MYC expression in this cohort harbors an SV between chr 8 and 4, with breakpoint on chr 8 located 50 Kb downstream of MYC. Similar SVs were detected in multiple NBL cell lines by WGS, which also express high levels of MYC. By analyzing Hi-C data from these cell lines, a new topologically associating domain (TAD) extending beyond the SV breakpoint was observed along the chimeric chromosome. This new TAD shows an aberrant interaction of a super-enhancer with a broad H3K27ac peak associated with HAND2/FBXO8 on chr 4 and the MYC promoter, demonstrating the rewired regulatory architecture introduced by SV as the driver for MYC dysregulation. In conclusion, our new GenomePaint interactive browser facilitates the analysis of SVs, CNAs and gene expression in concert studies by WGS and Hi-C in pediatric tumors. Coding mutations are rarely identified in many types of childhood tumors, even in the presence of pronounced chromosomal SVs, indicating new approaches are needed to unveil oncogenic mechanisms. GenomePaint provides an integrative analysis tool to evaluate the pathogenic basis underlying the often complex SVs in noncoding genome and function as oncogenic drivers in a large fraction of pediatric malignancies. Citation Format: Yu Liu, Xin Zhou, Jian Wang, Ying Shao, John Easton, Mark W. Zimmerman, Brian J. Abraham, A. Thomas Look, Jinghui Zhang. Exploring somatic DNA structural alteration and aberrant genomic interactions in cancer through GenomePaint [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 1287.