Francesca Petralia,Nicole Tignor,Boris Reva, et al., (2020) Cell 183, 1962-1985

We report a comprehensive proteogenomics analysis, including whole-genome sequencing, RNA sequencing, and proteomics and phosphoproteomics profiling, of 218 tumors across 7 histological types of childhood brain cancer: low-grade glioma (n = 93), ependymoma (32), high-grade glioma (25), medulloblastoma (22), ganglioglioma (18), craniopharyngioma (16), and atypical teratoid rhabdoid tumor (12). Proteomics data identify common biological themes that span histological boundaries, suggesting that treatments used for one histological type may be applied effectively to other tumors sharing similar proteomics features. Immune landscape characterization reveals diverse tumor microenvironments across and within diagnoses. Proteomics data further reveal functional effects of somatic mutations and copy number variations (CNVs) not evident in transcriptomics data. Kinase-substrate association and co-expression network analysis identify important biological mechanisms of tumorigenesis. This is the first large-scale proteogenomics analysis across traditional histological boundaries to uncover foundational pediatric brain tumor biology and inform rational treatment selection.

The Children's Brain Tumor Network (CBTN) and the Pacific Pediatric Neuro-Oncology Consortia (PNOC) are collaborative research consortia focused on identifying therapies for children with brain tumors (https://cbttc.org). The consortia have contributed a Pediatric Brain Tumor Atlas (PBTA) dataset, a cohort of 991 brain tumor subject clinical data, with associated whole genome sequencing and RNAseq hosted by the Gabriella Miller Kids First Data Resource (kidsfirstdrc.org) as part of the Gabriella Miller Kids First Pediatric Research Program (Kids First). Kids First is a Pan NIH Common Fund program dedicated to the development of large-scale data resources to help researchers uncover new insights into the biology of childhood cancer and structural birth defects (https://commonfund.nih.gov/KidsFirst).

Mass Spectrometry raw data generation along with preliminary analyses were performed at the Thermo Fisher Scientific Center for Multiplexed Proteomics (TCMP), Harvard Medical School (HMS) under the direction of Prof. Steven Gygi. Samples were prepared using the streamline (SL)-TMT protocol (Navarrete-Perea et al., 2018) and MS analysis was performed using the SPS-MS3 strategy (Ting et al., 2011) developed in the Gygi lab. Additional data analyses from the CPTAC Common Data Analysis Pipeline (Rudnick et al., 2016) and from the University of Michigan Proteomics and Integrative Bioinformatics Laboratory (https://github.com/Nesvilab) are also provided. All raw and processed genomic data, as well as pathology reports, radiology reports, MRIs, histology slide images are accessible via the Kids First DRC (Data Resource Center).

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