Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer

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; 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 Iavarone; 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

doi:10.1016/j.cell.2020.10.044

Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer

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. IveyJohn 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, 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 Iavarone, 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

Research output: Contribution to journal › Article › Research › peer-review

199 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1962-1985.e31
Number of pages	56
Journal	Cell
Volume	183
Issue number	7
DOIs	https://doi.org/10.1016/j.cell.2020.10.044
Publication status	Published - 23 Dec 2020
Externally published	Yes

Keywords

BRAF alteration
CPTAC
CTNNB1 mutation
kinase activity score
kinase substrate regulation
pediatric brain tumor
post-translational modification
proteomic cluster
recurrent versus primary tumors
tumor microenvironment

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1016/j.cell.2020.10.044Licence: CC BY-NC-ND

Cite this

Petralia, F., Tignor, N., Reva, B., Koptyra, M., Chowdhury, S., Rykunov, D., Krek, A., Ma, W., Zhu, Y., Ji, J., Calinawan, A., Whiteaker, J. R., Colaprico, A., Stathias, V., Omelchenko, T., Song, X., Raman, P., Guo, Y., Brown, M. A., ... Clinical Proteomic Tumor Analysis Consortium (2020). Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer. Cell, 183(7), 1962-1985.e31. https://doi.org/10.1016/j.cell.2020.10.044

@article{536f5ef87d334371834724d07c1363e7,

title = "Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer",

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.",

keywords = "BRAF alteration, CPTAC, CTNNB1 mutation, kinase activity score, kinase substrate regulation, pediatric brain tumor, post-translational modification, proteomic cluster, recurrent versus primary tumors, tumor microenvironment",

author = "Francesca Petralia and Nicole Tignor and Boris Reva and Mateusz Koptyra and Shrabanti Chowdhury and Dmitry Rykunov and Azra Krek and Weiping Ma and Yuankun Zhu and Jiayi Ji and Anna Calinawan and Whiteaker, {Jeffrey R.} and Antonio Colaprico and Vasileios Stathias and Tatiana Omelchenko and Xiaoyu Song and Pichai Raman and Yiran Guo and Brown, {Miguel A.} and Ivey, {Richard G.} and John Szpyt and {Guha Thakurta}, Sanjukta and Gritsenko, {Marina A.} and Weitz, {Karl K.} and Gonzalo Lopez and Selim Kalayci and G{\"u}m{\"u}{\c s}, {Zeynep H.} and Seungyeul Yoo and {da Veiga Leprevost}, Felipe and Chang, {Hui Yin} and Karsten Krug and Lizabeth Katsnelson and Ying Wang and Kennedy, {Jacob J.} and Voytovich, {Uliana J.} and Lei Zhao and Gaonkar, {Krutika S.} and Ennis, {Brian M.} and Bo Zhang and Valerie Baubet and Lamiya Tauhid and Lilly, {Jena V.} and Mason, {Jennifer L.} and Bailey Farrow and Nathan Young and Sarah Leary and Jamie Moon and Petyuk, {Vladislav A.} and Javad Nazarian and Adappa, {Nithin D.} and Palmer, {James N.} and Lober, {Robert M.} and Samuel Rivero-Hinojosa and Wang, {Liang Bo} and Wang, {Joshua M.} and Matilda Broberg and Chu, {Rosalie K.} and Moore, {Ronald J.} and Monroe, {Matthew E.} and Rui Zhao and Smith, {Richard D.} and Jun Zhu and Robles, {Ana I.} and Mehdi Mesri and Emily Boja and Tara Hiltke and Henry Rodriguez and Bing Zhang and Schadt, {Eric E.} and Mani, {D. R.} and Li Ding and Antonio Iavarone and Maciej Wiznerowicz and Stephan Sch{\"u}rer and Chen, {Xi S.} and Heath, {Allison P.} and Rokita, {Jo Lynne} and Nesvizhskii, {Alexey I.} and David Feny{\"o} and Rodland, {Karin D.} and Tao Liu and Gygi, {Steven P.} and Paulovich, {Amanda G.} and Resnick, {Adam C.} and Storm, {Phillip B.} and Rood, {Brian R.} and Pei Wang and Alicia Francis and Morgan, {Allison M.} and Waanders, {Angela J.} and Viaene, {Angela N.} and Buccoliero, {Anna Maria} and Chinnaiyan, {Arul M.} and Leonard, {Carina A.} and Kline, {Cassie N.} and Chiara Caporalini and Kinsinger, {Christopher R.} and Chunde Li and Kram, {David E.} and Derek Hanson and Elizabeth Appert and Kawaler, {Emily A.} and Raabe, {Eric H.} and Jackson, {Eric M.} and Greenfield, {Jeffrey P.} and Stone, {Gabrielle S.} and Gad Getz and Gerald Grant and Teo, {Guo Ci} and Pollack, {Ian F.} and Cain, {Jason E.} and Foster, {Jessica B.} and Phillips, {Joanna J.} and Palma, {July E.} and Ketchum, {Karen A.} and Ruggles, {Kelly V.} and Lili Blumenberg and Macintosh Cornwell and Mahdi Sarmady and Domagalski, {Marcin J.} and Cie{\'s}lik, {Marcin P.} and Mariarita Santi and Li, {Marilyn M.} and Ellis, {Matthew J.} and Wyczalkowski, {Matthew A.} and Meghan Connors and Mirko Scagnet and Nalin Gupta and Edwards, {Nathan J.} and Vitanza, {Nicholas A.} and Vaske, {Olena M.} and Oren Becher and McGarvey, {Peter B.} and Ron Firestein and Sabine Mueller and Winebrake, {Samuel G.} and Dhanasekaran, {Saravana Mohan} and Shuang Cai and Sonia Partap and Tatiana Patton and Toan Le and Lorentzen, {Travis D.} and Wenke Liu and Bocik, {William E.} and {Children's Brain Tumor Network} and {Clinical Proteomic Tumor Analysis Consortium}",

note = "Funding Information: This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) grants U24CA210993, U01 CA214114, U24CA210967, U24CA210954, U24CA210972, U24CA210955, U24CA210979, and R50 CA211499. We would like to thank the children and their families for donating tumor samples for this study, the Children's Brain Tumor Network, and Dr. David Stokes and the entire Biorepository Resource Center (BioRC) at Children's Hospital of Philadelphia. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The MS-based proteomic analysis of the Project Hope brain tumor samples was performed at the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy National Scientific User Facility located at the Pacific Northwest National Laboratory in Richland, WA, operated by the Battelle Memorial Institute for the DOE under contract DE-AC05-76RL01830. Study Conception & Design, H.R. A.C.R. A.G.P. S.P.G. P.B.S. B.R.R. and P.W.; Experiments and Data Collection, M.K. Y.Z. A.P.H. J.L.R. J.L.M. J.V.L. B.F. N.Y. A.C.R. S.P.G. S.G.T. J.S. A.G.P. U.J.V. L.Z. J.J.K. R.G.I. J.R.W. M.A.G. K.K.W. J.L.M. V.A.P. R.K.C. R.J.M. M.E.M. R.Z. R.D.S. K.D.R. and T.L.; Data Analysis, M.A.B. Y.G. K.S.G. P.R. B.M.E. B.Z. Y.Z. F.d.V.L. H.-Y.C. A.I.N. F.P. A.I. N.T. S.C. W.M. J.J. X.S. B.R. D.R. A.K. P.W. G.L. S.Y. J.Z, V.S. S.S. A. Colaprico. X.S.C. B.R. A.C.R. D.F. M.B. J.M.W. Y.W. L.-B.W. M.W. and L.K.; Sample Resources, A.C.R. J.V.L. J.L.M. P.B.S. V.B. and L.T.; Writing, F.P, N.T. M.K. S.C. W.M. M.A.B. K.S.G. J.L.R. D.R. A.K. X.S. J.J. S.Y. A.C.R. B.R.R. and P.W.; Visualization, S.K. G.L. Z.H.G. A. Calinawan, F.P. D.R. A.K. N.T. W.M. S.C. X.S. and J.J.; Supervision, P.W. B.R.R. A.C.R. A.G.P. S.P.G. J.L.R. Y.Z. M.K. A.P.H. P.B.S. and D.F.; Project Administration, P.W. H.R. E.B. T.H. M.M. F.P. N.T. B.R.R. and A.C.R.; Funding Acquisition, P.W. B.R.R. P.B.S. A.C.R. A.G.P. S.P.G. T.L. R.D.S. D.F. A.I.N. L.D. D.R.M. E.E.S. B.Z. and H.R. All authors contributed to data interpretation, manuscript editing, and revision. E.E.S. serves as chief executive officer for Sema4 and has an equity interest in this company. Funding Information: This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) grants U24CA210993 , U01 CA214114 , U24CA210967 , U24CA210954 , U24CA210972 , U24CA210955 , U24CA210979 , and R50 CA211499 . We would like to thank the children and their families for donating tumor samples for this study, the Children{\textquoteright}s Brain Tumor Network, and Dr. David Stokes and the entire Biorepository Resource Center (BioRC) at Children{\textquoteright}s Hospital of Philadelphia. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The MS-based proteomic analysis of the Project Hope brain tumor samples was performed at the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy National Scientific User Facility located at the Pacific Northwest National Laboratory in Richland, WA, operated by the Battelle Memorial Institute for the DOE under contract DE-AC05-76RL01830. Publisher Copyright: {\textcopyright} 2020 Elsevier Inc.",

year = "2020",

month = dec,

day = "23",

doi = "10.1016/j.cell.2020.10.044",

language = "English",

volume = "183",

pages = "1962--1985.e31",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "7",

}

Petralia, F, Tignor, N, Reva, B, Koptyra, M, Chowdhury, S, Rykunov, D, Krek, A, Ma, W, Zhu, Y, Ji, J, Calinawan, A, Whiteaker, JR, Colaprico, A, Stathias, V, Omelchenko, T, Song, X, Raman, P, Guo, Y, Brown, MA, Ivey, RG, Szpyt, J, Guha Thakurta, S, Gritsenko, MA, Weitz, KK, Lopez, G, Kalayci, S, Gümüş, ZH, Yoo, S, da Veiga Leprevost, F, Chang, HY, Krug, K, Katsnelson, L, Wang, Y, Kennedy, JJ, Voytovich, UJ, Zhao, L, Gaonkar, KS, Ennis, BM, Zhang, B, Baubet, V, Tauhid, L, Lilly, JV, Mason, JL, Farrow, B, Young, N, Leary, S, Moon, J, Petyuk, VA, Nazarian, J, Adappa, ND, Palmer, JN, Lober, RM, Rivero-Hinojosa, S, Wang, LB, Wang, JM, Broberg, M, Monroe, ME, Zhao, R, Smith, RD, Zhu, J, Robles, AI, Mesri, M, Boja, E, Hiltke, T, Rodriguez, H, Zhang, B, Schadt, EE, Mani, DR, Ding, L, Iavarone, A, Wiznerowicz, M, Schürer, S, Chen, XS, Heath, AP, Rokita, JL, Nesvizhskii, AI, Fenyö, D, Rodland, KD, Liu, T, Gygi, SP, Paulovich, AG, Resnick, AC, Storm, PB, Rood, BR, Wang, P, Children's Brain Tumor Network & Clinical Proteomic Tumor Analysis Consortium 2020, 'Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer', Cell, vol. 183, no. 7, pp. 1962-1985.e31. https://doi.org/10.1016/j.cell.2020.10.044

TY - JOUR

T1 - Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer

AU - Petralia, Francesca

AU - Tignor, Nicole

AU - Reva, Boris

AU - Koptyra, Mateusz

AU - Chowdhury, Shrabanti

AU - Rykunov, Dmitry

AU - Krek, Azra

AU - Ma, Weiping

AU - Zhu, Yuankun

AU - Ji, Jiayi

AU - Calinawan, Anna

AU - Whiteaker, Jeffrey R.

AU - Colaprico, Antonio

AU - Stathias, Vasileios

AU - Omelchenko, Tatiana

AU - Song, Xiaoyu

AU - Raman, Pichai

AU - Guo, Yiran

AU - Brown, Miguel A.

AU - Ivey, Richard G.

AU - Szpyt, John

AU - Guha Thakurta, Sanjukta

AU - Gritsenko, Marina A.

AU - Weitz, Karl K.

AU - Lopez, Gonzalo

AU - Kalayci, Selim

AU - Gümüş, Zeynep H.

AU - Yoo, Seungyeul

AU - da Veiga Leprevost, Felipe

AU - Chang, Hui Yin

AU - Krug, Karsten

AU - Katsnelson, Lizabeth

AU - Wang, Ying

AU - Kennedy, Jacob J.

AU - Voytovich, Uliana J.

AU - Zhao, Lei

AU - Gaonkar, Krutika S.

AU - Ennis, Brian M.

AU - Zhang, Bo

AU - Baubet, Valerie

AU - Tauhid, Lamiya

AU - Lilly, Jena V.

AU - Mason, Jennifer L.

AU - Farrow, Bailey

AU - Young, Nathan

AU - Leary, Sarah

AU - Moon, Jamie

AU - Petyuk, Vladislav A.

AU - Nazarian, Javad

AU - Adappa, Nithin D.

AU - Palmer, James N.

AU - Lober, Robert M.

AU - Rivero-Hinojosa, Samuel

AU - Wang, Liang Bo

AU - Wang, Joshua M.

AU - Broberg, Matilda

AU - Chu, Rosalie K.

AU - Moore, Ronald J.

AU - Monroe, Matthew E.

AU - Zhao, Rui

AU - Smith, Richard D.

AU - Zhu, Jun

AU - Robles, Ana I.

AU - Mesri, Mehdi

AU - Boja, Emily

AU - Hiltke, Tara

AU - Rodriguez, Henry

AU - Zhang, Bing

AU - Schadt, Eric E.

AU - Mani, D. R.

AU - Ding, Li

AU - Iavarone, Antonio

AU - Wiznerowicz, Maciej

AU - Schürer, Stephan

AU - Chen, Xi S.

AU - Heath, Allison P.

AU - Rokita, Jo Lynne

AU - Nesvizhskii, Alexey I.

AU - Fenyö, David

AU - Rodland, Karin D.

AU - Liu, Tao

AU - Gygi, Steven P.

AU - Paulovich, Amanda G.

AU - Resnick, Adam C.

AU - Storm, Phillip B.

AU - Rood, Brian R.

AU - Wang, Pei

AU - Francis, Alicia

AU - Morgan, Allison M.

AU - Waanders, Angela J.

AU - Viaene, Angela N.

AU - Buccoliero, Anna Maria

AU - Chinnaiyan, Arul M.

AU - Leonard, Carina A.

AU - Kline, Cassie N.

AU - Caporalini, Chiara

AU - Kinsinger, Christopher R.

AU - Li, Chunde

AU - Kram, David E.

AU - Hanson, Derek

AU - Appert, Elizabeth

AU - Kawaler, Emily A.

AU - Raabe, Eric H.

AU - Jackson, Eric M.

AU - Greenfield, Jeffrey P.

AU - Stone, Gabrielle S.

AU - Getz, Gad

AU - Grant, Gerald

AU - Teo, Guo Ci

AU - Pollack, Ian F.

AU - Cain, Jason E.

AU - Foster, Jessica B.

AU - Phillips, Joanna J.

AU - Palma, July E.

AU - Ketchum, Karen A.

AU - Ruggles, Kelly V.

AU - Blumenberg, Lili

AU - Cornwell, Macintosh

AU - Sarmady, Mahdi

AU - Domagalski, Marcin J.

AU - Cieślik, Marcin P.

AU - Santi, Mariarita

AU - Li, Marilyn M.

AU - Ellis, Matthew J.

AU - Wyczalkowski, Matthew A.

AU - Connors, Meghan

AU - Scagnet, Mirko

AU - Gupta, Nalin

AU - Edwards, Nathan J.

AU - Vitanza, Nicholas A.

AU - Vaske, Olena M.

AU - Becher, Oren

AU - McGarvey, Peter B.

AU - Firestein, Ron

AU - Mueller, Sabine

AU - Winebrake, Samuel G.

AU - Dhanasekaran, Saravana Mohan

AU - Cai, Shuang

AU - Partap, Sonia

AU - Patton, Tatiana

AU - Le, Toan

AU - Lorentzen, Travis D.

AU - Liu, Wenke

AU - Bocik, William E.

AU - Children's Brain Tumor Network

AU - Clinical Proteomic Tumor Analysis Consortium

N1 - Funding Information: This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) grants U24CA210993, U01 CA214114, U24CA210967, U24CA210954, U24CA210972, U24CA210955, U24CA210979, and R50 CA211499. We would like to thank the children and their families for donating tumor samples for this study, the Children's Brain Tumor Network, and Dr. David Stokes and the entire Biorepository Resource Center (BioRC) at Children's Hospital of Philadelphia. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The MS-based proteomic analysis of the Project Hope brain tumor samples was performed at the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy National Scientific User Facility located at the Pacific Northwest National Laboratory in Richland, WA, operated by the Battelle Memorial Institute for the DOE under contract DE-AC05-76RL01830. Study Conception & Design, H.R. A.C.R. A.G.P. S.P.G. P.B.S. B.R.R. and P.W.; Experiments and Data Collection, M.K. Y.Z. A.P.H. J.L.R. J.L.M. J.V.L. B.F. N.Y. A.C.R. S.P.G. S.G.T. J.S. A.G.P. U.J.V. L.Z. J.J.K. R.G.I. J.R.W. M.A.G. K.K.W. J.L.M. V.A.P. R.K.C. R.J.M. M.E.M. R.Z. R.D.S. K.D.R. and T.L.; Data Analysis, M.A.B. Y.G. K.S.G. P.R. B.M.E. B.Z. Y.Z. F.d.V.L. H.-Y.C. A.I.N. F.P. A.I. N.T. S.C. W.M. J.J. X.S. B.R. D.R. A.K. P.W. G.L. S.Y. J.Z, V.S. S.S. A. Colaprico. X.S.C. B.R. A.C.R. D.F. M.B. J.M.W. Y.W. L.-B.W. M.W. and L.K.; Sample Resources, A.C.R. J.V.L. J.L.M. P.B.S. V.B. and L.T.; Writing, F.P, N.T. M.K. S.C. W.M. M.A.B. K.S.G. J.L.R. D.R. A.K. X.S. J.J. S.Y. A.C.R. B.R.R. and P.W.; Visualization, S.K. G.L. Z.H.G. A. Calinawan, F.P. D.R. A.K. N.T. W.M. S.C. X.S. and J.J.; Supervision, P.W. B.R.R. A.C.R. A.G.P. S.P.G. J.L.R. Y.Z. M.K. A.P.H. P.B.S. and D.F.; Project Administration, P.W. H.R. E.B. T.H. M.M. F.P. N.T. B.R.R. and A.C.R.; Funding Acquisition, P.W. B.R.R. P.B.S. A.C.R. A.G.P. S.P.G. T.L. R.D.S. D.F. A.I.N. L.D. D.R.M. E.E.S. B.Z. and H.R. All authors contributed to data interpretation, manuscript editing, and revision. E.E.S. serves as chief executive officer for Sema4 and has an equity interest in this company. Funding Information: This work was supported by the National Cancer Institute (NCI) Clinical Proteomic Tumor Analysis Consortium (CPTAC) grants U24CA210993 , U01 CA214114 , U24CA210967 , U24CA210954 , U24CA210972 , U24CA210955 , U24CA210979 , and R50 CA211499 . We would like to thank the children and their families for donating tumor samples for this study, the Children’s Brain Tumor Network, and Dr. David Stokes and the entire Biorepository Resource Center (BioRC) at Children’s Hospital of Philadelphia. This work was supported in part through the computational resources and staff expertise provided by Scientific Computing at the Icahn School of Medicine at Mount Sinai. The MS-based proteomic analysis of the Project Hope brain tumor samples was performed at the Environmental Molecular Sciences Laboratory, a U.S. Department of Energy National Scientific User Facility located at the Pacific Northwest National Laboratory in Richland, WA, operated by the Battelle Memorial Institute for the DOE under contract DE-AC05-76RL01830. Publisher Copyright: © 2020 Elsevier Inc.

PY - 2020/12/23

Y1 - 2020/12/23

N2 - 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.

AB - 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.

KW - BRAF alteration

KW - CPTAC

KW - CTNNB1 mutation

KW - kinase activity score

KW - kinase substrate regulation

KW - pediatric brain tumor

KW - post-translational modification

KW - proteomic cluster

KW - recurrent versus primary tumors

KW - tumor microenvironment

UR - http://www.scopus.com/inward/record.url?scp=85097475909&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2020.10.044

DO - 10.1016/j.cell.2020.10.044

M3 - Article

C2 - 33242424

AN - SCOPUS:85097475909

SN - 0092-8674

VL - 183

SP - 1962-1985.e31

JO - Cell

JF - Cell

IS - 7

ER -

Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer

Abstract

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