Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas

Daniel J Brat, Roel G W Verhaak, Kenneth D Aldape, W K Alfred Yung, Sofie R Salama, Lee A D Cooper, Esther Rheinbay, C Ryan Miller, Mark Vitucci, Olena Morozova, A Gordon Robertson, Houtan Noushmehr, Peter W Laird, Andrew D Cherniack, Rehan Akbani, Jason T Huse, Giovanni Ciriello, Laila M Poisson, Jill S Barnholtz-Sloan, Mitchel S Berger, Cameron Brennan, Rivka R Colen, Howard Colman, Adam E Flanders, Caterina Giannini, Mia Grifford, Antonio Iavarone, Rajan Jain, Isaac Joseph, Jaegil Kim, Katayoon Kasaian, Tom Mikkelsen, Bradley A Murray, Brian Patrick O'Neill, Lior Pachter, Donald W Parsons, Carrie Sougnez, Erik P Sulman, Scott R Vandenberg, Erwin G Van Meir, Andreas von Deimling, Hailei Zhang, Daniel Crain, Kevin Lau, David Mallery, Scott Morris, Joseph Paulauskis, Robert Penny, Troy Shelton, Mark Sherman, Peggy Yena, Aaron Black, Jay Bowen, Katie Dicostanzo, Julie Gastier-Foster, Kristen M Leraas, Tara M Lichtenberg, Christopher R Pierson, Nilsa C Ramirez, Cynthia Taylor, Stephanie Weaver, Lisa Wise, Erik Zmuda, Tanja Davidsen, John A Demchok, Greg Eley, Martin L Ferguson, Carolyn M Hutter, Kenna R Mills Shaw, Bradley A Ozenberger, Margi Sheth, Heidi J Sofia, Roy Tarnuzzer, Zhining Wang, Liming Yang, Jean Claude Zenklusen, Brenda Ayala, Julien Baboud, Sudha Chudamani, Mark A Jensen, Jia Liu, Todd Pihl, Rohini Raman, Yunhu Wan, Ye Wu, Adrian Ally, J Todd Auman, Miruna Balasundaram, Saianand Balu, Stephen B Baylin, Rameen Beroukhim, Moiz S Bootwalla, Reanne Bowlby, Christopher A Bristow, Denise Brooks, Yaron Butterfield, Rebecca Carlsen, Scott Carter, Lynda Chin, Andy Chu, Eric Chuah, Kristian Cibulskis, Amanda Clarke, Simon G Coetzee, Noreen Dhalla, Tim Fennell, Sheila Fisher, Stacey Gabriel, Gad Getz, Richard Gibbs, Ranabir Guin, Angela Hadjipanayis, D Neil Hayes, Toshinori Hinoue, Katherine Hoadley, Robert A Holt, Alan P Hoyle, Stuart R Jefferys, Steven Jones, Corbin D Jones, Raju Kucherlapati, Phillip H Lai, Eric Lander, Semin Lee, Lee Lichtenstein, Yussanne Ma, Dennis T Maglinte, Harshad S Mahadeshwar, Marco A Marra, Michael Mayo, Shaowu Meng, Matthew L Meyerson, Piotr A Mieczkowski, Richard A Moore, Lisle E Mose, Andrew J Mungall, Angeliki Pantazi, Michael Parfenov, Peter J Park, Joel S Parker, Charles M Perou, Alexei Protopopov, Xiaojia Ren, Jeffrey Roach, Thaís S Sabedot, Jacqueline Schein, Steven E Schumacher, Jonathan G Seidman, Sahil Seth, Hui Shen, Janae V Simons, Payal Sipahimalani, Matthew G Soloway, Xingzhi Song, Huandong Sun, Barbara Tabak, Angela Tam, Donghui Tan, Jiabin Tang, Nina Thiessen, Timothy Triche, David J Van Den Berg, Umadevi Veluvolu, Scot Waring, Daniel J Weisenberger, Matthew D Wilkerson, Tina Wong, Junyuan Wu, Liu Xi, Andrew W Xu, Lixing Yang, Travis I Zack, Jianhua Zhang, B Arman Aksoy, Harindra Arachchi, Chris Benz, Brady Bernard, Daniel Carlin, Juok Cho, Daniel DiCara, Scott Frazer, Gregory N Fuller, JianJiong Gao, Nils Gehlenborg, David Haussler, David I Heiman, Lisa Iype, Anders Jacobsen, Zhenlin Ju, Sol Katzman, Hoon Kim, Theo Knijnenburg, Richard Bailey Kreisberg, Michael S Lawrence, William Lee, Kalle Leinonen, Pei Lin, Shiyun Ling, Wenbin Liu, Yingchun Liu, Yuexin Liu, Yiling Lu, Gordon Mills, Sam Ng, Michael S Noble, Evan Paull, Arvind Rao, Sheila Reynolds, Gordon Saksena, Zack Sanborn, Chris Sander, Nikolaus Schultz, Yasin Senbabaoglu, Ronglai Shen, Ilya Shmulevich, Rileen Sinha, Josh Stuart, S Onur Sumer, Yichao Sun, Natalie Tasman, Barry S Taylor, Doug Voet, Nils Weinhold, John N Weinstein, Da Yang, Kosuke Yoshihara, Siyuan Zheng, Wei Zhang, Lihua Zou, Ty Abel, Sara Sadeghi, Mark L Cohen, Jenny Eschbacher, Eyas M Hattab, Aditya Raghunathan, Matthew J Schniederjan, Dina Aziz, Gene Barnett, Wendi Barrett, Darell D Bigner, Lori Boice, Cathy Brewer, Chiara Calatozzolo, Benito Campos, Carlos Gilberto Carlotti, Timothy A Chan, Lucia Cuppini, Erin Curley, Stefania Cuzzubbo, Karen Devine, Francesco DiMeco, Rebecca Duell, J Bradley Elder, Ashley Fehrenbach, Gaetano Finocchiaro, William Friedman, Jordonna Fulop, Johanna Gardner, Beth Hermes, Christel Herold-Mende, Christine Jungk, Ady Kendler, Norman L Lehman, Eric Lipp, Ouida Liu, Randy Mandt, Mary McGraw, Roger Mclendon, Christopher McPherson, Luciano Neder, Phuong Nguyen, Ardene Noss, Raffaele Nunziata, Quinn T Ostrom, Cheryl Palmer, Alessandro Perin, Bianca Pollo, Alexander Potapov, Olga Potapova, W Kimryn Rathmell, Daniil Rotin, Lisa Scarpace, Cathy Schilero, Kelly Senecal, Kristen Shimmel, Vsevolod Shurkhay, Suzanne Sifri, Rosy Singh, Andrew E Sloan, Kathy Smolenski, Susan M Staugaitis, Ruth Steele, Leigh Thorne, Daniela P C Tirapelli, Andreas Unterberg, Mahitha Vallurupalli, Yun Wang, Ronald Warnick, Felicia Williams, Yingli Wolinsky, Sue Bell, Mara Rosenberg, Chip Stewart, Franklin Huang, Jonna L Grimsby, Amie J Radenbaugh, Jianan Zhang

Background Diffuse low-grade and intermediate-grade gliomas (which together make up the lower-grade gliomas, World Health Organization grades II and III) have highly variable clinical behavior that is not adequately predicted on the basis of histologic class. Some are indolent; others quickly progress to glioblastoma. The uncertainty is compounded by interobserver variability in histologic diagnosis. Mutations in IDH, TP53, and ATRX and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) have been implicated as clinically relevant markers of lower-grade gliomas. Methods We performed genomewide analyses of 293 lower-grade gliomas from adults, incorporating exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. These data were integrated and tested for correlation with clinical outcomes. Results Unsupervised clustering of mutations and data from RNA, DNA-copy-number, and DNA-methylation platforms uncovered concordant classification of three robust, nonoverlapping, prognostically significant subtypes of lower-grade glioma that were captured more accurately by IDH, 1p/19q, and TP53 status than by histologic class. Patients who had lower-grade gliomas with an IDH mutation and 1p/19q codeletion had the most favorable clinical outcomes. Their gliomas harbored mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Nearly all lower-grade gliomas with IDH mutations and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%). The large majority of lower-grade gliomas without an IDH mutation had genomic aberrations and clinical behavior strikingly similar to those found in primary glioblastoma. Conclusions The integration of genomewide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma. (Funded by the National Institutes of Health.).