Omics Core

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PROJECT SUMMARY/ABSTRACT – OMICS CORE The Developmental and Hyperactive Ras Tumor (DHART) SPORE was designed to integrate multiple research projects, all with the goal of identifying novel molecular therapeutic strategies for NF1-related malignancies. Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder, characterized by mutations in the NF1 gene, which encodes neurofibromin. Functional loss of neurofibromin, a Ras-GTPase activating protein (GAP) leads to hyperactive Ras signaling and dysregulation of multiple cell signaling pathways impacting cell proliferation and survival, such as Raf-MEK-ERK and PI3K-AKT-mTOR. The overall goal of the Omics Core (Core B) is to provide state-of-the-art support for research design consultation, performance of genomics and kinomics experiments, and integrated data analysis to DHART investigators to elucidate changes during NF1-related tumor development and in response to therapy. Built upon institutional genomics cores (Center for Medical Genomics), a newly established kinome laboratory, and a bioinformatics research center (Center for Computational Biology and Bioinformatics), Core B also interacts intensively with other cores for supporting the DHART investigators. Upon receipt of tracked samples (including mouse and human neurofibromas, JMML, GBM, and models of NF1-related subsequent neoplasms) from the Biospecimen/Pathology Core C, the following technologies and informatics platforms will be employed: 1. Core B will process samples for bulk RNA sequencing, single-cell RNA sequencing, whole exome sequencing, or targeted exome sequencing. 2. The Omics Core will analyze and annotate all RNAseq and exome sequencing data for transfer to Synapse, the Sage portal for data analysis 2. The Kinome Core will utilize established chemical proteomics methodology to provide functional, activity-based, global kinome profiles of NF1-related specimens, defining baseline kinome state, effects of specific genotype or genetic perturbations, and response to targeted inhibitors. 3. In collaboration with the Administrative Core A and Sage Bionetworks, integrative analyses will be performed to provide comprehensive molecular profiles of genotype-driven gene expression and functional kinome profiles. The profiles will be studied for both putative response biomarkers and for candidate therapeutic targets. Synapse, a web portal maintained by Sage will allow access by SPORE investigators of all data obtained by the Omics and Biospecimen/Pathology Cores, where findings will be annotated and made more broadly useful to all investigators involved in the SPORE. This data management portal will provide a unique resource for accessing and interpreting data generated by the three projects, Biospecimens and Pathology Core and Omics Core.