Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma

Michele Ceccarelli, Floris P. Barthel, Tathiane M. Malta, Thais S. Sabedot, Sofie R. Salama, Bradley A. Murray, Olena Morozova, Yulia Newton, Amie Radenbaugh, Stefano M. Pagnotta, Samreen Anjum, Jiguang Wang, Ganiraju Manyam, Pietro Zoppoli, Shiyun Ling, Arjun A. Rao, Mia Grifford, Andrew D. Cherniack, Hailei Zhang, Laila PoissonCarlos Gilberto Carlotti, Daniela Pretti Da Cunha Tirapelli, Arvind Rao, Tom Mikkelsen, Ching C. Lau, W. K.Alfred Yung, Raul Rabadan, Jason Huse, Daniel J. Brat, Norman L. Lehman, Jill S. Barnholtz-Sloan, Siyuan Zheng, Kenneth Hess, Ganesh Rao, Matthew Meyerson, Rameen Beroukhim, Lee Cooper, Rehan Akbani, Margaret Wrensch, David Haussler, Kenneth D. Aldape, Peter W. Laird, David H. Gutmann, Houtan Noushmehr, Harindra Arachchi, J. Todd Auman, Miruna Balasundaram, Saianand Balu, Gene Barnett, Stephen Baylin, Sue Bell, Christopher Benz, Natalie Bir, Keith L. Black, Tom Bodenheimer, Lori Boice, Moiz S. Bootwalla, Jay Bowen, Christopher A. Bristow, Yaron S.N. Butterfield, Qing Rong Chen, Lynda Chin, Juok Cho, Eric Chuah, Sudha Chudamani, Simon G. Coetzee, Mark L. Cohen, Howard Colman, Marta Couce, Fulvio D'Angelo, Tanja Davidsen, Amy Davis, John A. Demchok, Karen Devine, Li Ding, Rebecca Duell, J. Bradley Elder, Jennifer M. Eschbacher, Ashley Fehrenbach, Martin Ferguson, Scott Frazer, Gregory Fuller, Jordonna Fulop, Stacey B. Gabriel, Luciano Garofano, Julie M. Gastier-Foster, Nils Gehlenborg, Mark Gerken, Gad Getz, Caterina Giannini, William J. Gibson, Angela Hadjipanayis, D. Neil Hayes, David I. Heiman, Beth Hermes, Joe Hilty, Katherine A. Hoadley, Alan P. Hoyle, Mei Huang, Stuart R. Jefferys, Corbin D. Jones, Steven J.M. Jones, Zhenlin Ju, Alison Kastl, Ady Kendler, Jaegil Kim, Raju Kucherlapati, Phillip H. Lai, Michael S. Lawrence, Semin Lee, Kristen M. Leraas, Tara M. Lichtenberg, Pei Lin, Yuexin Liu, Jia Liu, Julia Y. Ljubimova, Yiling Lu, Yussanne Ma, Dennis T. Maglinte, Harshad S. Mahadeshwar, Marco A. Marra, Mary McGraw, Christopher McPherson, Shaowu Meng, Piotr A. Mieczkowski, C. Ryan Miller, Gordon B. Mills, Richard A. Moore, Lisle E. Mose, Andrew J. Mungall, Rashi Naresh, Theresa Naska, Luciano Neder, Michael S. Noble, Ardene Noss, Brian Patrick O'Neill, Quinn T. Ostrom, Cheryl Palmer, Angeliki Pantazi, Michael Parfenov, Peter J. Park, Joel S. Parker, Charles M. Perou, Christopher R. Pierson, Todd Pihl, Alexei Protopopov, Amie Radenbaugh, Nilsa C. Ramirez, W. Kimryn Rathmell, Xiaojia Ren, Jeffrey Roach, A. Gordon Robertson, Gordon Saksena, Jacqueline E. Schein, Steven E. Schumacher, Jonathan Seidman, Kelly Senecal, Sahil Seth, Hui Shen, Yan Shi, Juliann Shih, Kristen Shimmel, Hugues Sicotte, Suzanne Sifri, Tiago Silva, Janae V. Simons, Rosy Singh, Tara Skelly, Andrew E. Sloan, Heidi J. Sofia, Matthew G. Soloway, Xingzhi Song, Carrie Sougnez, Camila Souza, Susan M. Staugaitis, Huandong Sun, Charlie Sun, Donghui Tan, Jiabin Tang, Yufang Tang, Leigh Thorne, Felipe Amstalden Trevisan, Timothy Triche, David J. Van Den Berg, Umadevi Veluvolu, Doug Voet, Yunhu Wan, Zhining Wang, Ronald Warnick, John N. Weinstein, Daniel J. Weisenberger, Matthew D. Wilkerson, Felicia Williams, Lisa Wise, Yingli Wolinsky, Junyuan Wu, Andrew W. Xu, Lixing Yang, Liming Yang, Travis I. Zack, Jean C. Zenklusen, Jianhua Zhang, Wei Zhang, Jiashan Zhang, Erik Zmuda, Houtan Noushmehr, Antonio Iavarone, Roel G.W. Verhaak

Research output: Contribution to journalArticle

659 Scopus citations

Abstract

Summary Therapy development for adult diffuse glioma is hindered by incomplete knowledge of somatic glioma driving alterations and suboptimal disease classification. We defined the complete set of genes associated with 1,122 diffuse grade II-III-IV gliomas from The Cancer Genome Atlas and used molecular profiles to improve disease classification, identify molecular correlations, and provide insights into the progression from low- to high-grade disease. Whole-genome sequencing data analysis determined that ATRX but not TERT promoter mutations are associated with increased telomere length. Recent advances in glioma classification based on IDH mutation and 1p/19q co-deletion status were recapitulated through analysis of DNA methylation profiles, which identified clinically relevant molecular subsets. A subtype of IDH mutant glioma was associated with DNA demethylation and poor outcome; a group of IDH-wild-type diffuse glioma showed molecular similarity to pilocytic astrocytoma and relatively favorable survival. Understanding of cohesive disease groups may aid improved clinical outcomes.

Original languageEnglish (US)
Pages (from-to)550-563
Number of pages14
JournalCell
Volume164
Issue number3
DOIs
StatePublished - Jan 28 2016
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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  • Cite this

    Ceccarelli, M., Barthel, F. P., Malta, T. M., Sabedot, T. S., Salama, S. R., Murray, B. A., Morozova, O., Newton, Y., Radenbaugh, A., Pagnotta, S. M., Anjum, S., Wang, J., Manyam, G., Zoppoli, P., Ling, S., Rao, A. A., Grifford, M., Cherniack, A. D., Zhang, H., ... Verhaak, R. G. W. (2016). Molecular Profiling Reveals Biologically Discrete Subsets and Pathways of Progression in Diffuse Glioma. Cell, 164(3), 550-563. https://doi.org/10.1016/j.cell.2015.12.028