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Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer

Published in
Cell
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Francesca Petralia, Nicole Tignor, Boris Reva, Mateusz Koptyra, Shrabanti Chowdhury, Dmitry Rykunov, Azra Krek, Weiping Ma, Yuankun Zhu, Jiayi Ji, Anna Calinawan, Jeffrey R. Whiteaker, Antonio Colaprico, Vasileios Stathias, Tatiana Omelchenko, Xiaoyu Song, Pichai Raman, Yiran Guo, Miguel A. Brown, Richard G. Ivey, John Szpyt, Sanjukta Guha Thakurta, Marina A. Gritsenko, Karl K. Weitz, Gonzalo Lopez, Selim Kalayci, Zeynep H. Gümüş, Seungyeul Yoo, Felipe da Veiga Leprevost, Hui-Yin Chang, Karsten Krug, Lizabeth Katsnelson, Ying Wang, Jacob J. Kennedy, Uliana J. Voytovich, Lei Zhao, Krutika S. Gaonkar, Brian M. Ennis, Bo Zhang, Valerie Baubet, Lamiya Tauhid, Jena V. Lilly, Jennifer L. Mason, Bailey Farrow, Nathan Young, Sarah Leary, Jamie Moon, Vladislav A. Petyuk, Javad Nazarian, Nithin D. Adappa, James N. Palmer, Robert M. Lober, Samuel Rivero-Hinojosa, Liang-Bo Wang, Joshua M. Wang, Matilda Broberg, Rosalie K. Chu, Ronald J. Moore, Matthew E. Monroe, Rui Zhao, Richard D. Smith, Jun Zhu, Ana I. Robles, Mehdi Mesri, Emily Boja, Tara Hiltke, Henry Rodriguez, Bing Zhang, Eric E. Schadt, D.R. Mani, Li Ding, Antonio Lavarone, Maciej Wiznerowicz, Stephan Schürer, Xi S. Chen, Allison P. Heath, Jo Lynne Rokita, Alexey I. Nesvizhskii, David Fenyö, Karin D. Rodland, Tao Liu, Steven P. Gygi, Amanda G. Paulovich, Adam C. Resnick, Phillip B. Storm, Brian R. Rood, Pei Wang, Children’s Brain Tumor Network, Clinical Proteomic Tumor Analysis Consortium
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Abstract

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.

Highlights

  • Proteogenomics characterization of 218 pediatric brain tumor samples of 7 histologies
  • Proteomic clusters reveal actionable biological features spanning histological boundaries
  • Proteomics reveal downstream effects of DNA alterations not evident in transcriptomics
  • Kinase activity analyses provide insights into pathway activities and druggable targets