BACKGROUND: The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS: We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS: Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS: Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).
BACKGROUND: The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS: We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS: Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS: Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).
Authors: 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 Journal: N Engl J Med Date: 2015-06-10 Impact factor: 91.245
Authors: Simon N Stacey; Patrick Sulem; Aslaug Jonasdottir; Gisli Masson; Julius Gudmundsson; Daniel F Gudbjartsson; Olafur T Magnusson; Sigurjon A Gudjonsson; Bardur Sigurgeirsson; Kristin Thorisdottir; Rafn Ragnarsson; Kristrun R Benediktsdottir; Bjørn A Nexø; Anne Tjønneland; Kim Overvad; Peter Rudnai; Eugene Gurzau; Kvetoslava Koppova; Kari Hemminki; Cristina Corredera; Victoria Fuentelsaz; Pilar Grasa; Sebastian Navarrete; Fernando Fuertes; Maria D García-Prats; Enrique Sanambrosio; Angeles Panadero; Ana De Juan; Almudena Garcia; Fernando Rivera; Dolores Planelles; Virtudes Soriano; Celia Requena; Katja K Aben; Michelle M van Rossum; Ruben G H M Cremers; Inge M van Oort; Dick-Johan van Spronsen; Jack A Schalken; Wilbert H M Peters; Brian T Helfand; Jenny L Donovan; Freddie C Hamdy; Daniel Badescu; Ovidiu Codreanu; Mariana Jinga; Irma E Csiki; Vali Constantinescu; Paula Badea; Ioan N Mates; Daniela E Dinu; Adrian Constantin; Dana Mates; Sjofn Kristjansdottir; Bjarni A Agnarsson; Eirikur Jonsson; Rosa B Barkardottir; Gudmundur V Einarsson; Fridbjorn Sigurdsson; Pall H Moller; Tryggvi Stefansson; Trausti Valdimarsson; Oskar T Johannsson; Helgi Sigurdsson; Thorvaldur Jonsson; Jon G Jonasson; Laufey Tryggvadottir; Terri Rice; Helen M Hansen; Yuanyuan Xiao; Daniel H Lachance; Brian Patrick O Neill; Matthew L Kosel; Paul A Decker; Gudmar Thorleifsson; Hrefna Johannsdottir; Hafdis T Helgadottir; Asgeir Sigurdsson; Valgerdur Steinthorsdottir; Annika Lindblom; Robert S Sandler; Temitope O Keku; Karina Banasik; Torben Jørgensen; Daniel R Witte; Torben Hansen; Oluf Pedersen; Viorel Jinga; David E Neal; William J Catalona; Margaret Wrensch; John Wiencke; Robert B Jenkins; Eduardo Nagore; Ulla Vogel; Lambertus A Kiemeney; Rajiv Kumar; José I Mayordomo; Jon H Olafsson; Augustine Kong; Unnur Thorsteinsdottir; Thorunn Rafnar; Kari Stefansson Journal: Nat Genet Date: 2011-09-25 Impact factor: 38.330
Authors: Robert B Jenkins; Hilary Blair; Karla V Ballman; Caterina Giannini; Robert M Arusell; Mark Law; Heather Flynn; Sandra Passe; Sara Felten; Paul D Brown; Edward G Shaw; Jan C Buckner Journal: Cancer Res Date: 2006-10-15 Impact factor: 12.701
Authors: Suzette J Bielinski; High Seng Chai; Jyotishman Pathak; Jayant A Talwalkar; Paul J Limburg; Rachel E Gullerud; Hugues Sicotte; Eric W Klee; Jason L Ross; Jean-Pierre A Kocher; Iftikhar J Kullo; John A Heit; Gloria M Petersen; Mariza de Andrade; Christopher G Chute Journal: Mayo Clin Proc Date: 2011-06-06 Impact factor: 7.616
Authors: Houtan Noushmehr; Daniel J Weisenberger; Kristin Diefes; Heidi S Phillips; Kanan Pujara; Benjamin P Berman; Fei Pan; Christopher E Pelloski; Erik P Sulman; Krishna P Bhat; Roel G W Verhaak; Katherine A Hoadley; D Neil Hayes; Charles M Perou; Heather K Schmidt; Li Ding; Richard K Wilson; David Van Den Berg; Hui Shen; Henrik Bengtsson; Pierre Neuvial; Leslie M Cope; Jonathan Buckley; James G Herman; Stephen B Baylin; Peter W Laird; Kenneth Aldape Journal: Cancer Cell Date: 2010-04-15 Impact factor: 31.743
Authors: Robert B Jenkins; Margaret R Wrensch; Derek Johnson; Brooke L Fridley; Paul A Decker; Yuanyuan Xiao; Thomas M Kollmeyer; Amanda L Rynearson; Stephanie Fink; Terri Rice; Lucie S McCoy; Chandralekha Halder; Matthew L Kosel; Caterina Giannini; Tarik Tihan; Brian P O'Neill; Daniel H Lachance; Ping Yang; Joseph Wiemels; John K Wiencke Journal: Cancer Genet Date: 2011-01
Authors: Roel G W Verhaak; Katherine A Hoadley; Elizabeth Purdom; Victoria Wang; Yuan Qi; Matthew D Wilkerson; C Ryan Miller; Li Ding; Todd Golub; Jill P Mesirov; Gabriele Alexe; Michael Lawrence; Michael O'Kelly; Pablo Tamayo; Barbara A Weir; Stacey Gabriel; Wendy Winckler; Supriya Gupta; Lakshmi Jakkula; Heidi S Feiler; J Graeme Hodgson; C David James; Jann N Sarkaria; Cameron Brennan; Ari Kahn; Paul T Spellman; Richard K Wilson; Terence P Speed; Joe W Gray; Matthew Meyerson; Gad Getz; Charles M Perou; D Neil Hayes Journal: Cancer Cell Date: 2010-01-19 Impact factor: 31.743
Authors: Heidi S Phillips; Samir Kharbanda; Ruihuan Chen; William F Forrest; Robert H Soriano; Thomas D Wu; Anjan Misra; Janice M Nigro; Howard Colman; Liliana Soroceanu; P Mickey Williams; Zora Modrusan; Burt G Feuerstein; Ken Aldape Journal: Cancer Cell Date: 2006-03 Impact factor: 31.743
Authors: Sanjay Shete; Fay J Hosking; Lindsay B Robertson; Sara E Dobbins; Marc Sanson; Beatrice Malmer; Matthias Simon; Yannick Marie; Blandine Boisselier; Jean-Yves Delattre; Khe Hoang-Xuan; Soufiane El Hallani; Ahmed Idbaih; Diana Zelenika; Ulrika Andersson; Roger Henriksson; A Tommy Bergenheim; Maria Feychting; Stefan Lönn; Anders Ahlbom; Johannes Schramm; Michael Linnebank; Kari Hemminki; Rajiv Kumar; Sarah J Hepworth; Amy Price; Georgina Armstrong; Yanhong Liu; Xiangjun Gu; Robert Yu; Ching Lau; Minouk Schoemaker; Kenneth Muir; Anthony Swerdlow; Mark Lathrop; Melissa Bondy; Richard S Houlston Journal: Nat Genet Date: 2009-07-05 Impact factor: 38.330
Authors: Margaret Wrensch; Robert B Jenkins; Jeffrey S Chang; Ru-Fang Yeh; Yuanyuan Xiao; Paul A Decker; Karla V Ballman; Mitchel Berger; Jan C Buckner; Susan Chang; Caterina Giannini; Chandralekha Halder; Thomas M Kollmeyer; Matthew L Kosel; Daniel H LaChance; Lucie McCoy; Brian P O'Neill; Joe Patoka; Alexander R Pico; Michael Prados; Charles Quesenberry; Terri Rice; Amanda L Rynearson; Ivan Smirnov; Tarik Tihan; Joe Wiemels; Ping Yang; John K Wiencke Journal: Nat Genet Date: 2009-07-05 Impact factor: 38.330
Authors: Chenan Zhang; Adam J de Smith; Ivan V Smirnov; John K Wiencke; Joseph L Wiemels; John S Witte; Kyle M Walsh Journal: J Neurooncol Date: 2017-07-18 Impact factor: 4.130
Authors: Michael Wahl; Joanna J Phillips; Annette M Molinaro; Yi Lin; Arie Perry; Daphne A Haas-Kogan; Joseph F Costello; Manisha Dayal; Nicholas Butowski; Jennifer L Clarke; Michael Prados; Sarah Nelson; Mitchel S Berger; Susan M Chang Journal: Neuro Oncol Date: 2017-02-01 Impact factor: 12.300
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