Integrated Proteogenomic Characterization across Major Histological Types of Pediatric Brain Cancer

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), medulloblasto...

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Published in:	Cell Vol. 183; no. 7; pp. 1962 - 1985.e31
Main Authors:	Reva, Boris, Chowdhury, Shrabanti, Ji, Jiayi, Whiteaker, Jeffrey R., Colaprico, Antonio, Raman, Pichai, Guo, Yiran, Brown, Miguel A., Ivey, Richard G., Szpyt, John, Guha Thakurta, Sanjukta, Lopez, Gonzalo, Kalayci, Selim, Gümüş, Zeynep H., Yoo, Seungyeul, da Veiga Leprevost, Felipe, Katsnelson, Lizabeth, Wang, Ying, Kennedy, Jacob J., Voytovich, Uliana J., Zhao, Lei, Baubet, Valerie, Tauhid, Lamiya, Lilly, Jena V., Mason, Jennifer L., Farrow, Bailey, Young, Nathan, Leary, Sarah, Moon, Jamie, Petyuk, Vladislav A., Nazarian, Javad, Palmer, James N., Lober, Robert M., Rivero-Hinojosa, Samuel, Wang, Joshua M., Broberg, Matilda, Chu, Rosalie K., Moore, Ronald J., Monroe, Matthew E., Zhao, Rui, Zhu, Jun, Mesri, Mehdi, Boja, Emily, Hiltke, Tara, Rodriguez, Henry, Zhang, Bing, Mani, D.R., Iavarone, Antonio, Schürer, Stephan, Chen, Xi S., Heath, Allison P., Rokita, Jo Lynne, Nesvizhskii, Alexey I., Fenyö, David, Rodland, Karin D., Liu, Tao, Paulovich, Amanda G., Resnick, Adam C., Storm, Phillip B., Rood, Brian R., Wang, Pei, Morgan, Allison M., Waanders, Angela J., Buccoliero, Anna Maria, Leonard, Carina A., Kline, Cassie N., Li, Chunde, Kram, David E., Hanson, Derek, Appert, Elizabeth, Kawaler, Emily A., Raabe, Eric H., Jackson, Eric M., Greenfield, Jeffrey P., Pollack, Ian F., Cain, Jason E., Foster, Jessica B., Palma, July E., Ketchum, Karen A., Blumenberg, Lili, Cornwell, Macintosh, Sarmady, Mahdi, Domagalski, Marcin J., Cieślik, Marcin P., Li, Marilyn M., Wyczalkowski, Matthew A., Connors, Meghan, Gupta, Nalin, Edwards, Nathan J., Vaske, Olena M., Becher, Oren, Firestein, Ron, Mueller, Sabine, Winebrake, Samuel G., Dhanasekaran, Saravana Mohan, Cai, Shuang, Patton, Tatiana, Lorentzen, Travis D., Liu, Wenke, Bocik, William E.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 23-12-2020 Elsevier
Subjects:	BRAF alteration Brain Neoplasms - genetics Brain Neoplasms - immunology Brain Neoplasms - pathology Child CPTAC CTNNB1 mutation DNA Copy Number Variations - genetics Gene Expression Regulation, Neoplastic Gene Regulatory Networks Genome, Human Glioma - genetics Glioma - pathology Humans kinase activity score kinase substrate regulation Lymphocytes, Tumor-Infiltrating - immunology Mutation - genetics Neoplasm Grading Neoplasm Recurrence, Local - pathology pediatric brain tumor Phosphoproteins - metabolism Phosphorylation post-translational modification Proteogenomics proteomic cluster recurrent versus primary tumors RNA, Messenger - genetics RNA, Messenger - metabolism Transcriptome - genetics tumor microenvironment CTNNB1 mutation kinase activity score proteomic cluster kinase substrate regulation BRAF alteration post-translational modification tumor microenvironment recurrent versus primary tumors pediatric brain tumor CPTAC
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Summary:	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. [Display omitted] •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 Integrative proteogenomics analysis of pediatric tumors identifies common underlying biological processes and potential treatments as well as the functional effects of somatic mutations and CNVs driving tumorigenesis.
Bibliography:	USDOE Consortia Alexey I Nesvizhskii, Alicia Francis, Amanda G Paulovich, Ana I Robles, Anna Calinawan, Antonio Iavarone, Antonio Colaprico, Arul M Chinnaiyan, Azra Krek, Bing Zhang, Boris Reva, Christopher R Kinsinger, D. R Mani, David Fenyö, Dmitry Rykunov, Emily Boja, Emily A. Kawaler, Eric E Schadt, Felipe da Veiga Leprevost, Francesca Petralia, Gad Getz, Gonzalo Lopez, Guo Ci Teo, Henry Rodriguez, Hui-Yin Chang, Jacob J Kennedy, Jamie Moon, Jeffrey R Whiteaker, Jiayi Ji, John Spytz, Joshua Wang, Jun Zhu, Karen A Ketchum, Karin D Rodland, Karl K Weitz, Karsten Krug, Kelly V Ruggles, Lei Zhao, Li Ding, Liang-Bo Wang, Lili Blumenberg, Lizabeth Katsnelson, Maciej Wiznerowicz, MacIntosh Cornwell, Marcin J Domagalski, Marcin P Cieślik, Marina A Gritsenko, Matilda Broberg, Matthew J Ellis, Matthew A. Wyczalkowski, Matthew E Monroe, Mehdi Mesri, Nathan J Edwards, Nicole Tignor, Pei Wang, Peter B McGarvey, Richard G Ivey, Richard D Smith, Ronald J Moore, Rosalie K Chu, Rui Zhao, Sanjukta Guha Thakurta, Saravana Mohan Dhanasekaran, Selim Kalayci, Seungyeul Yoo, Shrabanti Chowdhury, Shuang Cai, Stephan Schürer, Steven P Gygi, Tao Liu, Tara Hiltke, Tatiana Omelchenko, Toan Le, Travis D Lorentzen, Uliana J Voytovich, Vasileios Stathias, Vladislav A Petyuk, Weiping Ma, Wenke Liu, William E Bocik, Xi Steven Chen, Xiaoyu Song, Ying Wang, Zeynep Gümüş. SECONDARY AUTHORS Clinical Proteomic Tumor Analysis Consortium (CPTAC) Study Conception & Design: H.R., A.C.R., A.G.P., S.P.G., P.B.S., B.R.R., P.W.; Performed Experiment and data collection: M.K., Y.Z., A.S.H., J.L.R., J.M., J.V.L., B.F., NY, A.C.R., S.P.G., S.G.T., J.S., A.G.P., T.D.L., U.J.V., L.Z., J.J.K., R.G.I., J.R.W., M.A.G., K.K.W., J.M., V.A.P., R.K.C., R.J.M., M.E.M., R.Z., R.D.S., K.D.R., T.L.; Data Analysis, M.A.B., Y.G., K.S.G., P.R., B.M.E., B.Z., Y.Z., F.D.L., H.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.C., X.S.C., B.R., A.C,R., D.F., M.B., J.W., J.M.W., Y.W., K.V.R., L.B., M.C., W.L.,E.K., L.K.; Sample Resources: A.C.R., J.V.L., J.M., P.B.S., V.B., 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., P.W. ; Visualization, S. K., G.L, Z.G, A.P.C., F.P., D.R., A.K., N.T.,W.M., S.C., X.S., 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.S.H., P.B.S., D. F.; Project Administration, P.W., H.R., E.B., T.H., C.R.K., M.M., F.P., N.T., B.R.R., 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., H.R.; All authors contributed to data interpretation, manuscript editing and revision. Adam C Resnick, Nithin D. Adappa, Elizabeth Appert, Valerie Baubet, Oren Becher, Miguel A. Brown, Anna Maria Buccoliero, Jason E. Cain, Chiara Caporalini, Meghan Connors, Brian M. Ennis, Bailey Farrow, Ron Firestein, Jessica B. Foster, Krutika S. Gaonkar, Gerald Grant, Jeffrey P. Greenfield, Yiran Guo, Nalin Gupta, Derek Hanson, Allison P. Heath, Eric M. Jackson, Cassie N. Kline, Mateusz Koptyra, David E. Kram, Sarah Leary, Carina A. Leonard, Chunde Li, Marilyn M. Li, Jena V. Lilly, Robert M. Lober, Jennifer L. Mason, Allison M. Morgan, Sabine Mueller, Javad Nazarian, Judy E. Palma, James Palmer, Sonia Partap, Tatiana Patton, Joanna J. Phillips, Ian F. Pollack, Eric H. Raabe, Pichai Raman, Samuel Rivero-Hinojosa, Jo Lynne Rokita, Brian R. Rood, Mariarita Santi, Mahdi Sarmady, Mirko Scagnet, Gabrielle S. Stone, Phillip B. Storm, Lamiya Tauhid, Olena M. Vaske, Angela N. Viaene, Nicholas A. Vitanza, Angela J. Waanders, Samuel G. Winebrake, Nathan Young, Bo Zhang, Yuankun Zhu. AUTHOR CONTRIBUTIONS Alicia Francis, Allison M. Morgan, Angela J. Waanders, Angela N. Viaene, Anna Maria Buccoliero, Arul M. Chinnaiyan, Carina A. Leonard, Cassie N. Kline, Chiara Caporalini, Christopher R. Kinsinger, Chunde Li, David E. Kram, Derek Hanson, Elizabeth Appert, Emily A. Kawaler, Eric H. Raabe, Eric M. Jackson, Jeffrey P. Greenfield, Gabrielle S. Stone, Gad Getz, Gerald Grant, Guo Ci Teo, Ian F. Pollack, Jason E. Cain, Jessica B. Foster, Joanna J. Phillips, July E. Palma, Karen A. Ketchum, Kelly V. Ruggles, Lili Blumenberg, Macintosh Cornwell, Mahdi Sarmady, Marcin J. Domagalski, Marcin P. Cieślik, Mariarita Santi, Marilyn M. Li, Matthew J. Ellis, Matthew A. Wyczalkowski, Meghan Connors, Mirko Scagnet, Nalin Gupta, Nathan J. Edwards, Nicholas A. Vitanza, Olena M. Vaske, Oren Becher, Peter B. McGarvey, Ron Firestein, Sabine Mueller, Samuel G. Winebrake, Saravana Mohan Dhanasekaran, Shuang Cai, Sonia Partap, Tatiana Patton, Toan Le, Travis D. Lorentzen, Wenke Liu, William E. Bocik. Children’s Brain Tumor Tissue Consortium (CBTTC)
ISSN:	0092-8674 1097-4172
DOI:	10.1016/j.cell.2020.10.044