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

Authors
Michele Ceccarelli,Floris Barthel
Tathiane Malta,Thaís Sabedot,Sofie Salama,Bradley Murray,Olena Morozova,Yulia Newton,Amie Radenbaugh,Stefano Pagnotta,Samreen Anjum,Jiguang Wang,Ganiraju Manyam,Pietro Zoppoli,Shiyun Ling,Arjun Rao,Mia Grifford,Andrew Cherniack,Hailei Zhang,Laila Poisson,Carlos Carlotti,Daniela Tirapelli,Arvind Rao,Tom Mikkelsen,Ching Lau,W. Yung,Raúl Rabadán,Jason Huse,Daniel Brat,Norman Lehman,Jill Barnholtz‐Sloan,Siyuan Zheng,Kenneth Hess,Ganesh Rao,Matthew Meyerson,Rameen Beroukhim,Lee Cooper,Rehan Akbani,Margaret Wrensch,David Haussler,Kenneth Aldape,Peter Laird,David Gutmann,Houtan Noushmehr,Antonio Iavarone,Roel Verhaak,Harindra Arachchi,J. Auman,Miruna Balasundaram,Saianand Balu,Gene Barnett,Stephen Baylin,Sue Bell,Christopher Benz,Natalie Bir,Keith Black,Tom Bodenheimer,Lori Boice,Moiz Bootwalla,Jay Bowen,Christopher Bristow,Yaron Butterfield,Qing‐Rong Chen,Lynda Chin,Juok Cho,Eric Chuah,Sudha Chudamani,Simon Coetzee,Mark Cohen,Howard Colman,Marta Couce,Fulvio D’Angelo,Tanja Davidsen,Amy Davis,John Demchok,Karen Devine,Li Ding,Rebecca Duell,J. Elder,Jennifer Eschbacher,Ashley Fehrenbach,Martin Ferguson,Scott Frazer,Gregory Fuller,Jordonna Fulop,Stacey Gabriel,Luciano Garofano,Julie Gastier-Foster,Nils Gehlenborg,Mark Gerken,Gad Getz,Caterina Giannini,William Gibson,Angela Hadjipanayis,D. Hayes,David Heiman,Beth Hermes,Joe Hilty,Katherine Hoadley,Alan Hoyle,Mei Huang,Stuart Jefferys,Corbin Jones,Steven Jones,Zhenlin Ju,Alison Kastl,Ady Kendler,Jaegil Kim,Raju Kucherlapati,Phillip Lai,Michael Lawrence,Semin Lee,Kristen Leraas,Tara Lichtenberg,Pei Lin,Yuexin Liu,Jia Liu,Julia Ljubimova,Yiling Lu,Yussanne Ma,Dennis Maglinte,Harshad Mahadeshwar,Marco Marra,Mary McGraw,Christopher McPherson,Shaowu Meng,Piotr Mieczkowski,C. Miller,Gordon Mills,Richard Moore,Lisle Mose,Andrew Mungall,Rashi Naresh,Theresa Naska,Luciano Neder,Michael Noble,Ardene Noss,Brian O’Neill,Quinn Ostrom,Cheryl Palmer,Angeliki Pantazi,Michael Parfenov,Peter Park,Joel Parker,Charles Perou,Christopher Pierson,Todd Pihl,Alexei Protopopov,Nilsa Ramirez,W. Rathmell,Xiaojia Ren,Jeffrey Roach,A. Robertson,Gordon Saksena,Jacqueline Schein,Steven Schumacher,Jonathan Seidman,Kelly Senecal,Sahil Seth,Hui Shen,Yan Shi,Juliann Shih,Kristen Shimmel,Hugues Sicotte,Suzanne Sifri,Tiago Silva,Janae Simons,Rosy Singh,Tara Skelly,Andrew Sloan,Heidi Sofia,Matthew Soloway,Xingzhi Song,Carrie Sougnez,Camila Souza,Susan Staugaitis,Huandong Sun,Charlie Sun,Donghui Tan,Jiabin Tang,Yufang Tang,Leigh Thorne,Felipe Trevisan,Timothy Triche,David Berg,Umadevi Veluvolu,Doug Voet,Yunhu Wan,Zhining Wang,Ronald Warnick,John Weinstein,Daniel Weisenberger,Matthew Wilkerson,Cecilia Williams,Lisa Wise,Yingli Wolinsky,Junyuan Wu,Andrew Xu,Lixing Yang,Liming Yang,Travis Zack,Jean Zenklusen,Jianhua Zhang,Wei Zhang,Jiashan Zhang,Erik Zmuda,Raùl Rabadàn
+205 authors
,Arnoud Boot
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Jan 1, 2016
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Abstract

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.

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