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 & 287 others 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, Jian Jiong 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

Research output: Contribution to journalArticle

  • 568 Citations

Abstract

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.)

LanguageEnglish (US)
Pages2481-2498
Number of pages18
JournalNew England Journal of Medicine
Volume372
Issue number26
DOIs
StatePublished - Jun 25 2015

Fingerprint

Glioma
Mutation
Glioblastoma
DNA Methylation
Exome
Observer Variation
National Institutes of Health (U.S.)
MicroRNAs
Uncertainty
Cluster Analysis
Chromosomes
RNA
Messenger RNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Brat, D. J., Verhaak, R. G. W., Aldape, K. D., Yung, W. K. A., Salama, S. R., Cooper, L. A. D., ... Zhang, J. (2015). Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. New England Journal of Medicine, 372(26), 2481-2498. DOI: 10.1056/NEJMoa1402121

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

In: New England Journal of Medicine, Vol. 372, No. 26, 25.06.2015, p. 2481-2498.

Research output: Contribution to journalArticle

Brat, DJ, Verhaak, RGW, Aldape, KD, Yung, WKA, Salama, SR, Cooper, LAD, Rheinbay, E, Miller, CR, Vitucci, M, Morozova, O, Robertson, AG, Noushmehr, H, Laird, PW, Cherniack, AD, Akbani, R, Huse, JT, Ciriello, G, Poisson, LM, Barnholtz-Sloan, JS, Berger, MS, Brennan, C, Colen, RR, Colman, H, Flanders, AE, Giannini, C, Grifford, M, Iavarone, A, Jain, R, Joseph, I, Kim, J, Kasaian, K, Mikkelsen, T, Murray, BA, O'Neill, BP, Pachter, L, Parsons, DW, Sougnez, C, Sulman, EP, Vandenberg, SR, Van Meir, EG, Von Deimling, A, Zhang, H, Crain, D, Lau, K, Mallery, D, Morris, S, Paulauskis, J, Penny, R, Shelton, T, Sherman, M, Yena, P, Black, A, Bowen, J, Dicostanzo, K, Gastier-Foster, J, Leraas, KM, Lichtenberg, TM, Pierson, CR, Ramirez, NC, Taylor, C, Weaver, S, Wise, L, Zmuda, E, Davidsen, T, Demchok, JA, Eley, G, Ferguson, ML, Hutter, CM, Shaw, KRM, Ozenberger, BA, Sheth, M, Sofia, HJ, Tarnuzzer, R, Wang, Z, Yang, L, Zenklusen, JC, Ayala, B, Baboud, J, Chudamani, S, Jensen, MA, Liu, J, Pihl, T, Raman, R, Wan, Y, Wu, Y, Ally, A, Auman, JT, Balasundaram, M, Balu, S, Baylin, SB, Beroukhim, R, Bootwalla, MS, Bowlby, R, Bristow, CA, Brooks, D, Butterfield, Y, Carlsen, R, Carter, S, Chin, L, Chu, A, Chuah, E, Cibulskis, K, Clarke, A, Coetzee, SG, Dhalla, N, Fennell, T, Fisher, S, Gabriel, S, Getz, G, Gibbs, R, Guin, R, Hadjipanayis, A, Hayes, DN, Hinoue, T, Hoadley, K, Holt, RA, Hoyle, AP, Jefferys, SR, Jones, S, Jones, CD, Kucherlapati, R, Lai, PH, Lander, E, Lee, S, Lichtenstein, L, Ma, Y, Maglinte, DT, Mahadeshwar, HS, Marra, MA, Mayo, M, Meng, S, Meyerson, ML, Mieczkowski, PA, Moore, RA, Mose, LE, Mungall, AJ, Pantazi, A, Parfenov, M, Park, PJ, Parker, JS, Perou, CM, Protopopov, A, Ren, X, Roach, J, Sabedot, TS, Schein, J, Schumacher, SE, Seidman, JG, Seth, S, Shen, H, Simons, JV, Sipahimalani, P, Soloway, MG, Song, X, Sun, H, Tabak, B, Tam, A, Tan, D, Tang, J, Thiessen, N, Triche, T, Van Den Berg, DJ, Veluvolu, U, Waring, S, Weisenberger, DJ, Wilkerson, MD, Wong, T, Wu, J, Xi, L, Xu, AW, Yang, L, Zack, TI, Zhang, J, Aksoy, BA, Arachchi, H, Benz, C, Bernard, B, Carlin, D, Cho, J, DiCara, D, Frazer, S, Fuller, GN, Gao, JJ, Gehlenborg, N, Haussler, D, Heiman, DI, Iype, L, Jacobsen, A, Ju, Z, Katzman, S, Kim, H, Knijnenburg, T, Kreisberg, RB, Lawrence, MS, Lee, W, Leinonen, K, Lin, P, Ling, S, Liu, W, Liu, Y, Liu, Y, Lu, Y, Mills, G, Ng, S, Noble, MS, Paull, E, Rao, A, Reynolds, S, Saksena, G, Sanborn, Z, Sander, C, Schultz, N, Senbabaoglu, Y, Shen, R, Shmulevich, I, Sinha, R, Stuart, J, Sumer, SO, Sun, Y, Tasman, N, Taylor, BS, Voet, D, Weinhold, N, Weinstein, JN, Yang, D, Yoshihara, K, Zheng, S, Zhang, W, Zou, L, Abel, T, Sadeghi, S, Cohen, ML, Eschbacher, J, Hattab, EM, Raghunathan, A, Schniederjan, MJ, Aziz, D, Barnett, G, Barrett, W, Bigner, DD, Boice, L, Brewer, C, Calatozzolo, C, Campos, B, Carlotti, CG, Chan, TA, Cuppini, L, Curley, E, Cuzzubbo, S, Devine, K, DiMeco, F, Duell, R, Elder, JB, Fehrenbach, A, Finocchiaro, G, Friedman, W, Fulop, J, Gardner, J, Hermes, B, Herold-Mende, C, Jungk, C, Kendler, A, Lehman, NL, Lipp, E, Liu, O, Mandt, R, McGraw, M, Mclendon, R, McPherson, C, Neder, L, Nguyen, P, Noss, A, Nunziata, R, Ostrom, QT, Palmer, C, Perin, A, Pollo, B, Potapov, A, Potapova, O, Rathmell, WK, Rotin, D, Scarpace, L, Schilero, C, Senecal, K, Shimmel, K, Shurkhay, V, Sifri, S, Singh, R, Sloan, AE, Smolenski, K, Staugaitis, SM, Steele, R, Thorne, L, Tirapelli, DPC, Unterberg, A, Vallurupalli, M, Wang, Y, Warnick, R, Williams, F, Wolinsky, Y, Bell, S, Rosenberg, M, Stewart, C, Huang, F, Grimsby, JL, Radenbaugh, AJ & Zhang, J 2015, 'Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas' New England Journal of Medicine, vol. 372, no. 26, pp. 2481-2498. DOI: 10.1056/NEJMoa1402121
Brat DJ, Verhaak RGW, Aldape KD, Yung WKA, Salama SR, Cooper LAD et al. Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. New England Journal of Medicine. 2015 Jun 25;372(26):2481-2498. Available from, DOI: 10.1056/NEJMoa1402121
Brat, Daniel J. ; Verhaak, Roel G.W. ; Aldape, Kenneth D. ; Yung, W. K.Alfred ; Salama, Sofie R. ; Cooper, Lee A.D. ; Rheinbay, Esther ; Miller, C. Ryan ; Vitucci, Mark ; Morozova, Olena ; Robertson, A. Gordon ; Noushmehr, Houtan ; Laird, Peter W. ; Cherniack, Andrew D. ; Akbani, Rehan ; Huse, Jason T. ; Ciriello, Giovanni ; Poisson, Laila M. ; Barnholtz-Sloan, Jill S. ; Berger, Mitchel S. ; Brennan, Cameron ; Colen, Rivka R. ; Colman, Howard ; Flanders, Adam E. ; Giannini, Caterina ; Grifford, Mia ; Iavarone, Antonio ; Jain, Rajan ; Joseph, Isaac ; Kim, Jaegil ; Kasaian, Katayoon ; Mikkelsen, Tom ; Murray, Bradley A. ; O'Neill, Brian Patrick ; Pachter, Lior ; Parsons, Donald W. ; Sougnez, Carrie ; Sulman, Erik P. ; Vandenberg, Scott R. ; Van Meir, Erwin G. ; Von Deimling, Andreas ; Zhang, Hailei ; Crain, Daniel ; Lau, Kevin ; Mallery, David ; Morris, Scott ; Paulauskis, Joseph ; Penny, Robert ; Shelton, Troy ; Sherman, Mark ; Yena, Peggy ; Black, Aaron ; Bowen, Jay ; Dicostanzo, Katie ; Gastier-Foster, Julie ; Leraas, Kristen M. ; Lichtenberg, Tara M. ; Pierson, Christopher R. ; Ramirez, Nilsa C. ; Taylor, Cynthia ; Weaver, Stephanie ; Wise, Lisa ; Zmuda, Erik ; Davidsen, Tanja ; Demchok, John A. ; Eley, Greg ; Ferguson, Martin L. ; Hutter, Carolyn M. ; Shaw, Kenna R.Mills ; Ozenberger, Bradley A. ; Sheth, Margi ; Sofia, Heidi J. ; Tarnuzzer, Roy ; Wang, Zhining ; Yang, Liming ; Zenklusen, Jean Claude ; Ayala, Brenda ; Baboud, Julien ; Chudamani, Sudha ; Jensen, Mark A. ; Liu, Jia ; Pihl, Todd ; Raman, Rohini ; Wan, Yunhu ; Wu, Ye ; Ally, Adrian ; Auman, J. Todd ; Balasundaram, Miruna ; Balu, Saianand ; Baylin, Stephen B. ; Beroukhim, Rameen ; Bootwalla, Moiz S. ; Bowlby, Reanne ; Bristow, Christopher A. ; Brooks, Denise ; Butterfield, Yaron ; Carlsen, Rebecca ; Carter, Scott ; Chin, Lynda ; Chu, Andy ; Chuah, Eric ; Cibulskis, Kristian ; Clarke, Amanda ; Coetzee, Simon G. ; Dhalla, Noreen ; Fennell, Tim ; Fisher, Sheila ; Gabriel, Stacey ; Getz, Gad ; Gibbs, Richard ; Guin, Ranabir ; Hadjipanayis, Angela ; Hayes, D. Neil ; Hinoue, Toshinori ; Hoadley, Katherine ; Holt, Robert A. ; Hoyle, Alan P. ; Jefferys, Stuart R. ; Jones, Steven ; Jones, Corbin D. ; Kucherlapati, Raju ; Lai, Phillip H. ; Lander, Eric ; Lee, Semin ; Lichtenstein, Lee ; Ma, Yussanne ; Maglinte, Dennis T. ; Mahadeshwar, Harshad S. ; Marra, Marco A. ; Mayo, Michael ; Meng, Shaowu ; Meyerson, Matthew L. ; Mieczkowski, Piotr A. ; Moore, Richard A. ; Mose, Lisle E. ; Mungall, Andrew J. ; Pantazi, Angeliki ; Parfenov, Michael ; Park, Peter J. ; Parker, Joel S. ; Perou, Charles M. ; Protopopov, Alexei ; Ren, Xiaojia ; Roach, Jeffrey ; Sabedot, Thaís S. ; Schein, Jacqueline ; Schumacher, Steven E. ; Seidman, Jonathan G. ; Seth, Sahil ; Shen, Hui ; Simons, Janae V. ; Sipahimalani, Payal ; Soloway, Matthew G. ; Song, Xingzhi ; Sun, Huandong ; Tabak, Barbara ; Tam, Angela ; Tan, Donghui ; Tang, Jiabin ; Thiessen, Nina ; Triche, Timothy ; Van Den Berg, David J. ; Veluvolu, Umadevi ; Waring, Scot ; Weisenberger, Daniel J. ; Wilkerson, Matthew D. ; Wong, Tina ; Wu, Junyuan ; Xi, Liu ; Xu, Andrew W. ; Yang, Lixing ; Zack, Travis I. ; Zhang, Jianhua ; Aksoy, B. Arman ; Arachchi, Harindra ; Benz, Chris ; Bernard, Brady ; Carlin, Daniel ; Cho, Juok ; DiCara, Daniel ; Frazer, Scott ; Fuller, Gregory N. ; Gao, Jian Jiong ; Gehlenborg, Nils ; Haussler, David ; Heiman, David I. ; Iype, Lisa ; Jacobsen, Anders ; Ju, Zhenlin ; Katzman, Sol ; Kim, Hoon ; Knijnenburg, Theo ; Kreisberg, Richard Bailey ; Lawrence, Michael S. ; Lee, William ; Leinonen, Kalle ; Lin, Pei ; Ling, Shiyun ; Liu, Wenbin ; Liu, Yingchun ; Liu, Yuexin ; Lu, Yiling ; Mills, Gordon ; Ng, Sam ; Noble, Michael S. ; Paull, Evan ; Rao, Arvind ; Reynolds, Sheila ; Saksena, Gordon ; Sanborn, Zack ; Sander, Chris ; Schultz, Nikolaus ; Senbabaoglu, Yasin ; Shen, Ronglai ; Shmulevich, Ilya ; Sinha, Rileen ; Stuart, Josh ; Sumer, S. Onur ; Sun, Yichao ; Tasman, Natalie ; Taylor, Barry S. ; Voet, Doug ; Weinhold, Nils ; Weinstein, John N. ; Yang, Da ; Yoshihara, Kosuke ; Zheng, Siyuan ; Zhang, Wei ; Zou, Lihua ; Abel, Ty ; Sadeghi, Sara ; Cohen, Mark L. ; Eschbacher, Jenny ; Hattab, Eyas M. ; Raghunathan, Aditya ; Schniederjan, Matthew J. ; Aziz, Dina ; Barnett, Gene ; Barrett, Wendi ; Bigner, Darell D. ; Boice, Lori ; Brewer, Cathy ; Calatozzolo, Chiara ; Campos, Benito ; Carlotti, Carlos Gilberto ; Chan, Timothy A. ; Cuppini, Lucia ; Curley, Erin ; Cuzzubbo, Stefania ; Devine, Karen ; DiMeco, Francesco ; Duell, Rebecca ; Elder, J. Bradley ; Fehrenbach, Ashley ; Finocchiaro, Gaetano ; Friedman, William ; Fulop, Jordonna ; Gardner, Johanna ; Hermes, Beth ; Herold-Mende, Christel ; Jungk, Christine ; Kendler, Ady ; Lehman, Norman L. ; Lipp, Eric ; Liu, Ouida ; Mandt, Randy ; McGraw, Mary ; Mclendon, Roger ; McPherson, Christopher ; Neder, Luciano ; Nguyen, Phuong ; Noss, Ardene ; Nunziata, Raffaele ; Ostrom, Quinn T. ; Palmer, Cheryl ; Perin, Alessandro ; Pollo, Bianca ; Potapov, Alexander ; Potapova, Olga ; Rathmell, W. Kimryn ; Rotin, Daniil ; Scarpace, Lisa ; Schilero, Cathy ; Senecal, Kelly ; Shimmel, Kristen ; Shurkhay, Vsevolod ; Sifri, Suzanne ; Singh, Rosy ; Sloan, Andrew E. ; Smolenski, Kathy ; Staugaitis, Susan M. ; Steele, Ruth ; Thorne, Leigh ; Tirapelli, Daniela P.C. ; Unterberg, Andreas ; Vallurupalli, Mahitha ; Wang, Yun ; Warnick, Ronald ; Williams, Felicia ; Wolinsky, Yingli ; Bell, Sue ; Rosenberg, Mara ; Stewart, Chip ; Huang, Franklin ; Grimsby, Jonna L. ; Radenbaugh, Amie J. ; Zhang, Jianan. / Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. In: New England Journal of Medicine. 2015 ; Vol. 372, No. 26. pp. 2481-2498
@article{0c4c3df03fd0486587d690b8297526bd,
title = "Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas",
abstract = "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.)",
author = "Brat, {Daniel J.} and Verhaak, {Roel G.W.} and Aldape, {Kenneth D.} and Yung, {W. K.Alfred} and Salama, {Sofie R.} and Cooper, {Lee A.D.} and Esther Rheinbay and Miller, {C. Ryan} and Mark Vitucci and Olena Morozova and Robertson, {A. Gordon} and Houtan Noushmehr and Laird, {Peter W.} and Cherniack, {Andrew D.} and Rehan Akbani and Huse, {Jason T.} and Giovanni Ciriello and Poisson, {Laila M.} and Barnholtz-Sloan, {Jill S.} and Berger, {Mitchel S.} and Cameron Brennan and Colen, {Rivka R.} and Howard Colman and Flanders, {Adam E.} and Caterina Giannini and Mia Grifford and Antonio Iavarone and Rajan Jain and Isaac Joseph and Jaegil Kim and Katayoon Kasaian and Tom Mikkelsen and Murray, {Bradley A.} and O'Neill, {Brian Patrick} and Lior Pachter and Parsons, {Donald W.} and Carrie Sougnez and Sulman, {Erik P.} and Vandenberg, {Scott R.} and {Van Meir}, {Erwin G.} and {Von Deimling}, Andreas and Hailei Zhang and Daniel Crain and Kevin Lau and David Mallery and Scott Morris and Joseph Paulauskis and Robert Penny and Troy Shelton and Mark Sherman and Peggy Yena and Aaron Black and Jay Bowen and Katie Dicostanzo and Julie Gastier-Foster and Leraas, {Kristen M.} and Lichtenberg, {Tara M.} and Pierson, {Christopher R.} and Ramirez, {Nilsa C.} and Cynthia Taylor and Stephanie Weaver and Lisa Wise and Erik Zmuda and Tanja Davidsen and Demchok, {John A.} and Greg Eley and Ferguson, {Martin L.} and Hutter, {Carolyn M.} and Shaw, {Kenna R.Mills} and Ozenberger, {Bradley A.} and Margi Sheth and Sofia, {Heidi J.} and Roy Tarnuzzer and Zhining Wang and Liming Yang and Zenklusen, {Jean Claude} and Brenda Ayala and Julien Baboud and Sudha Chudamani and Jensen, {Mark A.} and Jia Liu and Todd Pihl and Rohini Raman and Yunhu Wan and Ye Wu and Adrian Ally and Auman, {J. Todd} and Miruna Balasundaram and Saianand Balu and Baylin, {Stephen B.} and Rameen Beroukhim and Bootwalla, {Moiz S.} and Reanne Bowlby and Bristow, {Christopher A.} and Denise Brooks and Yaron Butterfield and Rebecca Carlsen and Scott Carter and Lynda Chin and Andy Chu and Eric Chuah and Kristian Cibulskis and Amanda Clarke and Coetzee, {Simon G.} and Noreen Dhalla and Tim Fennell and Sheila Fisher and Stacey Gabriel and Gad Getz and Richard Gibbs and Ranabir Guin and Angela Hadjipanayis and Hayes, {D. Neil} and Toshinori Hinoue and Katherine Hoadley and Holt, {Robert A.} and Hoyle, {Alan P.} and Jefferys, {Stuart R.} and Steven Jones and Jones, {Corbin D.} and Raju Kucherlapati and Lai, {Phillip H.} and Eric Lander and Semin Lee and Lee Lichtenstein and Yussanne Ma and Maglinte, {Dennis T.} and Mahadeshwar, {Harshad S.} and Marra, {Marco A.} and Michael Mayo and Shaowu Meng and Meyerson, {Matthew L.} and Mieczkowski, {Piotr A.} and Moore, {Richard A.} and Mose, {Lisle E.} and Mungall, {Andrew J.} and Angeliki Pantazi and Michael Parfenov and Park, {Peter J.} and Parker, {Joel S.} and Perou, {Charles M.} and Alexei Protopopov and Xiaojia Ren and Jeffrey Roach and Sabedot, {Tha{\'i}s S.} and Jacqueline Schein and Schumacher, {Steven E.} and Seidman, {Jonathan G.} and Sahil Seth and Hui Shen and Simons, {Janae V.} and Payal Sipahimalani and Soloway, {Matthew G.} and Xingzhi Song and Huandong Sun and Barbara Tabak and Angela Tam and Donghui Tan and Jiabin Tang and Nina Thiessen and Timothy Triche and {Van Den Berg}, {David J.} and Umadevi Veluvolu and Scot Waring and Weisenberger, {Daniel J.} and Wilkerson, {Matthew D.} and Tina Wong and Junyuan Wu and Liu Xi and Xu, {Andrew W.} and Lixing Yang and Zack, {Travis I.} and Jianhua Zhang and Aksoy, {B. Arman} and Harindra Arachchi and Chris Benz and Brady Bernard and Daniel Carlin and Juok Cho and Daniel DiCara and Scott Frazer and Fuller, {Gregory N.} and Gao, {Jian Jiong} and Nils Gehlenborg and David Haussler and Heiman, {David I.} and Lisa Iype and Anders Jacobsen and Zhenlin Ju and Sol Katzman and Hoon Kim and Theo Knijnenburg and Kreisberg, {Richard Bailey} and Lawrence, {Michael S.} and William Lee and Kalle Leinonen and Pei Lin and Shiyun Ling and Wenbin Liu and Yingchun Liu and Yuexin Liu and Yiling Lu and Gordon Mills and Sam Ng and Noble, {Michael S.} and Evan Paull and Arvind Rao and Sheila Reynolds and Gordon Saksena and Zack Sanborn and Chris Sander and Nikolaus Schultz and Yasin Senbabaoglu and Ronglai Shen and Ilya Shmulevich and Rileen Sinha and Josh Stuart and Sumer, {S. Onur} and Yichao Sun and Natalie Tasman and Taylor, {Barry S.} and Doug Voet and Nils Weinhold and Weinstein, {John N.} and Da Yang and Kosuke Yoshihara and Siyuan Zheng and Wei Zhang and Lihua Zou and Ty Abel and Sara Sadeghi and Cohen, {Mark L.} and Jenny Eschbacher and Hattab, {Eyas M.} and Aditya Raghunathan and Schniederjan, {Matthew J.} and Dina Aziz and Gene Barnett and Wendi Barrett and Bigner, {Darell D.} and Lori Boice and Cathy Brewer and Chiara Calatozzolo and Benito Campos and Carlotti, {Carlos Gilberto} and Chan, {Timothy A.} and Lucia Cuppini and Erin Curley and Stefania Cuzzubbo and Karen Devine and Francesco DiMeco and Rebecca Duell and Elder, {J. Bradley} and Ashley Fehrenbach and Gaetano Finocchiaro and William Friedman and Jordonna Fulop and Johanna Gardner and Beth Hermes and Christel Herold-Mende and Christine Jungk and Ady Kendler and Lehman, {Norman L.} and Eric Lipp and Ouida Liu and Randy Mandt and Mary McGraw and Roger Mclendon and Christopher McPherson and Luciano Neder and Phuong Nguyen and Ardene Noss and Raffaele Nunziata and Ostrom, {Quinn T.} and Cheryl Palmer and Alessandro Perin and Bianca Pollo and Alexander Potapov and Olga Potapova and Rathmell, {W. Kimryn} and Daniil Rotin and Lisa Scarpace and Cathy Schilero and Kelly Senecal and Kristen Shimmel and Vsevolod Shurkhay and Suzanne Sifri and Rosy Singh and Sloan, {Andrew E.} and Kathy Smolenski and Staugaitis, {Susan M.} and Ruth Steele and Leigh Thorne and Tirapelli, {Daniela P.C.} and Andreas Unterberg and Mahitha Vallurupalli and Yun Wang and Ronald Warnick and Felicia Williams and Yingli Wolinsky and Sue Bell and Mara Rosenberg and Chip Stewart and Franklin Huang and Grimsby, {Jonna L.} and Radenbaugh, {Amie J.} and Jianan Zhang",
year = "2015",
month = "6",
day = "25",
doi = "10.1056/NEJMoa1402121",
language = "English (US)",
volume = "372",
pages = "2481--2498",
journal = "New England Journal of Medicine",
issn = "0028-4793",
publisher = "Massachussetts Medical Society",
number = "26",

}

TY - JOUR

T1 - Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas

AU - Brat,Daniel J.

AU - Verhaak,Roel G.W.

AU - Aldape,Kenneth D.

AU - Yung,W. K.Alfred

AU - Salama,Sofie R.

AU - Cooper,Lee A.D.

AU - Rheinbay,Esther

AU - Miller,C. Ryan

AU - Vitucci,Mark

AU - Morozova,Olena

AU - Robertson,A. Gordon

AU - Noushmehr,Houtan

AU - Laird,Peter W.

AU - Cherniack,Andrew D.

AU - Akbani,Rehan

AU - Huse,Jason T.

AU - Ciriello,Giovanni

AU - Poisson,Laila M.

AU - Barnholtz-Sloan,Jill S.

AU - Berger,Mitchel S.

AU - Brennan,Cameron

AU - Colen,Rivka R.

AU - Colman,Howard

AU - Flanders,Adam E.

AU - Giannini,Caterina

AU - Grifford,Mia

AU - Iavarone,Antonio

AU - Jain,Rajan

AU - Joseph,Isaac

AU - Kim,Jaegil

AU - Kasaian,Katayoon

AU - Mikkelsen,Tom

AU - Murray,Bradley A.

AU - O'Neill,Brian Patrick

AU - Pachter,Lior

AU - Parsons,Donald W.

AU - Sougnez,Carrie

AU - Sulman,Erik P.

AU - Vandenberg,Scott R.

AU - Van Meir,Erwin G.

AU - Von Deimling,Andreas

AU - Zhang,Hailei

AU - Crain,Daniel

AU - Lau,Kevin

AU - Mallery,David

AU - Morris,Scott

AU - Paulauskis,Joseph

AU - Penny,Robert

AU - Shelton,Troy

AU - Sherman,Mark

AU - Yena,Peggy

AU - Black,Aaron

AU - Bowen,Jay

AU - Dicostanzo,Katie

AU - Gastier-Foster,Julie

AU - Leraas,Kristen M.

AU - Lichtenberg,Tara M.

AU - Pierson,Christopher R.

AU - Ramirez,Nilsa C.

AU - Taylor,Cynthia

AU - Weaver,Stephanie

AU - Wise,Lisa

AU - Zmuda,Erik

AU - Davidsen,Tanja

AU - Demchok,John A.

AU - Eley,Greg

AU - Ferguson,Martin L.

AU - Hutter,Carolyn M.

AU - Shaw,Kenna R.Mills

AU - Ozenberger,Bradley A.

AU - Sheth,Margi

AU - Sofia,Heidi J.

AU - Tarnuzzer,Roy

AU - Wang,Zhining

AU - Yang,Liming

AU - Zenklusen,Jean Claude

AU - Ayala,Brenda

AU - Baboud,Julien

AU - Chudamani,Sudha

AU - Jensen,Mark A.

AU - Liu,Jia

AU - Pihl,Todd

AU - Raman,Rohini

AU - Wan,Yunhu

AU - Wu,Ye

AU - Ally,Adrian

AU - Auman,J. Todd

AU - Balasundaram,Miruna

AU - Balu,Saianand

AU - Baylin,Stephen B.

AU - Beroukhim,Rameen

AU - Bootwalla,Moiz S.

AU - Bowlby,Reanne

AU - Bristow,Christopher A.

AU - Brooks,Denise

AU - Butterfield,Yaron

AU - Carlsen,Rebecca

AU - Carter,Scott

AU - Chin,Lynda

AU - Chu,Andy

AU - Chuah,Eric

AU - Cibulskis,Kristian

AU - Clarke,Amanda

AU - Coetzee,Simon G.

AU - Dhalla,Noreen

AU - Fennell,Tim

AU - Fisher,Sheila

AU - Gabriel,Stacey

AU - Getz,Gad

AU - Gibbs,Richard

AU - Guin,Ranabir

AU - Hadjipanayis,Angela

AU - Hayes,D. Neil

AU - Hinoue,Toshinori

AU - Hoadley,Katherine

AU - Holt,Robert A.

AU - Hoyle,Alan P.

AU - Jefferys,Stuart R.

AU - Jones,Steven

AU - Jones,Corbin D.

AU - Kucherlapati,Raju

AU - Lai,Phillip H.

AU - Lander,Eric

AU - Lee,Semin

AU - Lichtenstein,Lee

AU - Ma,Yussanne

AU - Maglinte,Dennis T.

AU - Mahadeshwar,Harshad S.

AU - Marra,Marco A.

AU - Mayo,Michael

AU - Meng,Shaowu

AU - Meyerson,Matthew L.

AU - Mieczkowski,Piotr A.

AU - Moore,Richard A.

AU - Mose,Lisle E.

AU - Mungall,Andrew J.

AU - Pantazi,Angeliki

AU - Parfenov,Michael

AU - Park,Peter J.

AU - Parker,Joel S.

AU - Perou,Charles M.

AU - Protopopov,Alexei

AU - Ren,Xiaojia

AU - Roach,Jeffrey

AU - Sabedot,Thaís S.

AU - Schein,Jacqueline

AU - Schumacher,Steven E.

AU - Seidman,Jonathan G.

AU - Seth,Sahil

AU - Shen,Hui

AU - Simons,Janae V.

AU - Sipahimalani,Payal

AU - Soloway,Matthew G.

AU - Song,Xingzhi

AU - Sun,Huandong

AU - Tabak,Barbara

AU - Tam,Angela

AU - Tan,Donghui

AU - Tang,Jiabin

AU - Thiessen,Nina

AU - Triche,Timothy

AU - Van Den Berg,David J.

AU - Veluvolu,Umadevi

AU - Waring,Scot

AU - Weisenberger,Daniel J.

AU - Wilkerson,Matthew D.

AU - Wong,Tina

AU - Wu,Junyuan

AU - Xi,Liu

AU - Xu,Andrew W.

AU - Yang,Lixing

AU - Zack,Travis I.

AU - Zhang,Jianhua

AU - Aksoy,B. Arman

AU - Arachchi,Harindra

AU - Benz,Chris

AU - Bernard,Brady

AU - Carlin,Daniel

AU - Cho,Juok

AU - DiCara,Daniel

AU - Frazer,Scott

AU - Fuller,Gregory N.

AU - Gao,Jian Jiong

AU - Gehlenborg,Nils

AU - Haussler,David

AU - Heiman,David I.

AU - Iype,Lisa

AU - Jacobsen,Anders

AU - Ju,Zhenlin

AU - Katzman,Sol

AU - Kim,Hoon

AU - Knijnenburg,Theo

AU - Kreisberg,Richard Bailey

AU - Lawrence,Michael S.

AU - Lee,William

AU - Leinonen,Kalle

AU - Lin,Pei

AU - Ling,Shiyun

AU - Liu,Wenbin

AU - Liu,Yingchun

AU - Liu,Yuexin

AU - Lu,Yiling

AU - Mills,Gordon

AU - Ng,Sam

AU - Noble,Michael S.

AU - Paull,Evan

AU - Rao,Arvind

AU - Reynolds,Sheila

AU - Saksena,Gordon

AU - Sanborn,Zack

AU - Sander,Chris

AU - Schultz,Nikolaus

AU - Senbabaoglu,Yasin

AU - Shen,Ronglai

AU - Shmulevich,Ilya

AU - Sinha,Rileen

AU - Stuart,Josh

AU - Sumer,S. Onur

AU - Sun,Yichao

AU - Tasman,Natalie

AU - Taylor,Barry S.

AU - Voet,Doug

AU - Weinhold,Nils

AU - Weinstein,John N.

AU - Yang,Da

AU - Yoshihara,Kosuke

AU - Zheng,Siyuan

AU - Zhang,Wei

AU - Zou,Lihua

AU - Abel,Ty

AU - Sadeghi,Sara

AU - Cohen,Mark L.

AU - Eschbacher,Jenny

AU - Hattab,Eyas M.

AU - Raghunathan,Aditya

AU - Schniederjan,Matthew J.

AU - Aziz,Dina

AU - Barnett,Gene

AU - Barrett,Wendi

AU - Bigner,Darell D.

AU - Boice,Lori

AU - Brewer,Cathy

AU - Calatozzolo,Chiara

AU - Campos,Benito

AU - Carlotti,Carlos Gilberto

AU - Chan,Timothy A.

AU - Cuppini,Lucia

AU - Curley,Erin

AU - Cuzzubbo,Stefania

AU - Devine,Karen

AU - DiMeco,Francesco

AU - Duell,Rebecca

AU - Elder,J. Bradley

AU - Fehrenbach,Ashley

AU - Finocchiaro,Gaetano

AU - Friedman,William

AU - Fulop,Jordonna

AU - Gardner,Johanna

AU - Hermes,Beth

AU - Herold-Mende,Christel

AU - Jungk,Christine

AU - Kendler,Ady

AU - Lehman,Norman L.

AU - Lipp,Eric

AU - Liu,Ouida

AU - Mandt,Randy

AU - McGraw,Mary

AU - Mclendon,Roger

AU - McPherson,Christopher

AU - Neder,Luciano

AU - Nguyen,Phuong

AU - Noss,Ardene

AU - Nunziata,Raffaele

AU - Ostrom,Quinn T.

AU - Palmer,Cheryl

AU - Perin,Alessandro

AU - Pollo,Bianca

AU - Potapov,Alexander

AU - Potapova,Olga

AU - Rathmell,W. Kimryn

AU - Rotin,Daniil

AU - Scarpace,Lisa

AU - Schilero,Cathy

AU - Senecal,Kelly

AU - Shimmel,Kristen

AU - Shurkhay,Vsevolod

AU - Sifri,Suzanne

AU - Singh,Rosy

AU - Sloan,Andrew E.

AU - Smolenski,Kathy

AU - Staugaitis,Susan M.

AU - Steele,Ruth

AU - Thorne,Leigh

AU - Tirapelli,Daniela P.C.

AU - Unterberg,Andreas

AU - Vallurupalli,Mahitha

AU - Wang,Yun

AU - Warnick,Ronald

AU - Williams,Felicia

AU - Wolinsky,Yingli

AU - Bell,Sue

AU - Rosenberg,Mara

AU - Stewart,Chip

AU - Huang,Franklin

AU - Grimsby,Jonna L.

AU - Radenbaugh,Amie J.

AU - Zhang,Jianan

PY - 2015/6/25

Y1 - 2015/6/25

N2 - 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.)

AB - 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.)

UR - http://www.scopus.com/inward/record.url?scp=84932628860&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84932628860&partnerID=8YFLogxK

U2 - 10.1056/NEJMoa1402121

DO - 10.1056/NEJMoa1402121

M3 - Article

VL - 372

SP - 2481

EP - 2498

JO - New England Journal of Medicine

T2 - New England Journal of Medicine

JF - New England Journal of Medicine

SN - 0028-4793

IS - 26

ER -