Kevin Shee1, Meagan Chambers2, Edward G Hughes3, Damian A Almiron, Sophie J Deharvengt2,3, Donald Green3, Joel A Lefferts2,3, Angeline S Andrew2,4, William F Hickey2,3, Gregory J Tsongalis5,6. 1. Geisel School of Medicine At Dartmouth, Hanover, NH, Germany. Kevin.Shee.MED@dartmouth.edu. 2. Geisel School of Medicine At Dartmouth, Hanover, NH, Germany. 3. Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, 03756, Lebanon, NH, Germany. 4. Department of Neurology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, Germany. 5. Geisel School of Medicine At Dartmouth, Hanover, NH, Germany. Gregory.J.Tsongalis@hitchcock.org. 6. Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, 03756, Lebanon, NH, Germany. Gregory.J.Tsongalis@hitchcock.org.
Abstract
INTRODUCTION: Recent molecular characterization of gliomas has uncovered somatic gene variation and DNA methylation changes that are associated with etiology, prognosis, and therapeutic response. Here we describe genomic profiling of gliomas assessed for associations between genetic mutations and patient outcomes, including overall survival (OS) and recurrence-free survival (RFS). METHODS: Mutations in a 50-gene cancer panel, 1p19q co-deletion, and MGMT promoter methylation (MGMT methylation) status were obtained from tumor tissue of 293 glioma patients. Multivariable regression models for overall survival (OS) and recurrence-free survival (RFS) were constructed for MGMT methylation, 1p19q co-deletion, and gene mutations controlling for age, treatment status, and WHO grade. RESULTS: Mutational profiles of gliomas significantly differed based on WHO Grade, such as high prevalence of BRAF V600E, IDH1, and PTEN mutations in WHO Grade I, II/III, and IV tumors, respectively. In multivariate regression analysis, MGMT methylation and IDH1 mutations were significantly associated with improved OS (HR = 0.44, p = 0.0004 and HR = 0.21, p = 0.007, respectively), while FLT3 and TP53 mutations were significantly associated with poorer OS (HR = 19.46, p < 0.0001 and HR = 1.67, p = 0.014, respectively). MGMT methylation and IDH1 mutations were the only significant alterations associated with improved RFS in the model (HR = 0.42, p < 0.0001 and HR = 0.37, p = 0.002, respectively). These factors were then included in a combined model, which significantly exceeded the predictive value of the base model alone (age, surgery, radiation, chemo, grade) (likelihood ratio test OS p = 1.64 × 10-8 and RFS p = 3.80 × 10-7). CONCLUSIONS: This study highlights the genomic landscape of gliomas in a single-institution cohort and identifies a novel association between FLT3 mutation and OS in gliomas.
INTRODUCTION: Recent molecular characterization of gliomas has uncovered somatic gene variation and DNA methylation changes that are associated with etiology, prognosis, and therapeutic response. Here we describe genomic profiling of gliomas assessed for associations between genetic mutations and patient outcomes, including overall survival (OS) and recurrence-free survival (RFS). METHODS: Mutations in a 50-gene cancer panel, 1p19q co-deletion, and MGMT promoter methylation (MGMT methylation) status were obtained from tumor tissue of 293 gliomapatients. Multivariable regression models for overall survival (OS) and recurrence-free survival (RFS) were constructed for MGMT methylation, 1p19q co-deletion, and gene mutations controlling for age, treatment status, and WHO grade. RESULTS: Mutational profiles of gliomas significantly differed based on WHO Grade, such as high prevalence of BRAFV600E, IDH1, and PTEN mutations in WHO Grade I, II/III, and IV tumors, respectively. In multivariate regression analysis, MGMT methylation and IDH1 mutations were significantly associated with improved OS (HR = 0.44, p = 0.0004 and HR = 0.21, p = 0.007, respectively), while FLT3 and TP53 mutations were significantly associated with poorer OS (HR = 19.46, p < 0.0001 and HR = 1.67, p = 0.014, respectively). MGMT methylation and IDH1 mutations were the only significant alterations associated with improved RFS in the model (HR = 0.42, p < 0.0001 and HR = 0.37, p = 0.002, respectively). These factors were then included in a combined model, which significantly exceeded the predictive value of the base model alone (age, surgery, radiation, chemo, grade) (likelihood ratio test OS p = 1.64 × 10-8 and RFS p = 3.80 × 10-7). CONCLUSIONS: This study highlights the genomic landscape of gliomas in a single-institution cohort and identifies a novel association between FLT3 mutation and OS in gliomas.
Entities:
Keywords:
Glioma; Molecular profiles; Next generation sequencing; Targeted therapy
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: David N Louis; Arie Perry; Guido Reifenberger; Andreas von Deimling; Dominique Figarella-Branger; Webster K Cavenee; Hiroko Ohgaki; Otmar D Wiestler; Paul Kleihues; David W Ellison Journal: Acta Neuropathol Date: 2016-05-09 Impact factor: 17.088
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: Monika E Hegi; Annie-Claire Diserens; Thierry Gorlia; Marie-France Hamou; Nicolas de Tribolet; Michael Weller; Johan M Kros; Johannes A Hainfellner; Warren Mason; Luigi Mariani; Jacoline E C Bromberg; Peter Hau; René O Mirimanoff; J Gregory Cairncross; Robert C Janzer; Roger Stupp Journal: N Engl J Med Date: 2005-03-10 Impact factor: 91.245
Authors: Dominik Sturm; Hendrik Witt; Volker Hovestadt; Dong-Anh Khuong-Quang; David T W Jones; Carolin Konermann; Elke Pfaff; Martje Tönjes; Martin Sill; Sebastian Bender; Marcel Kool; Marc Zapatka; Natalia Becker; Manuela Zucknick; Thomas Hielscher; Xiao-Yang Liu; Adam M Fontebasso; Marina Ryzhova; Steffen Albrecht; Karine Jacob; Marietta Wolter; Martin Ebinger; Martin U Schuhmann; Timothy van Meter; Michael C Frühwald; Holger Hauch; Arnulf Pekrun; Bernhard Radlwimmer; Tim Niehues; Gregor von Komorowski; Matthias Dürken; Andreas E Kulozik; Jenny Madden; Andrew Donson; Nicholas K Foreman; Rachid Drissi; Maryam Fouladi; Wolfram Scheurlen; Andreas von Deimling; Camelia Monoranu; Wolfgang Roggendorf; Christel Herold-Mende; Andreas Unterberg; Christof M Kramm; Jörg Felsberg; Christian Hartmann; Benedikt Wiestler; Wolfgang Wick; Till Milde; Olaf Witt; Anders M Lindroth; Jeremy Schwartzentruber; Damien Faury; Adam Fleming; Magdalena Zakrzewska; Pawel P Liberski; Krzysztof Zakrzewski; Peter Hauser; Miklos Garami; Almos Klekner; Laszlo Bognar; Sorana Morrissy; Florence Cavalli; Michael D Taylor; Peter van Sluis; Jan Koster; Rogier Versteeg; Richard Volckmann; Tom Mikkelsen; Kenneth Aldape; Guido Reifenberger; V Peter Collins; Jacek Majewski; Andrey Korshunov; Peter Lichter; Christoph Plass; Nada Jabado; Stefan M Pfister Journal: Cancer Cell Date: 2012-10-16 Impact factor: 31.743
Authors: Roger Stupp; Monika E Hegi; Warren P Mason; Martin J van den Bent; Martin J B Taphoorn; Robert C Janzer; Samuel K Ludwin; Anouk Allgeier; Barbara Fisher; Karl Belanger; Peter Hau; Alba A Brandes; Johanna Gijtenbeek; Christine Marosi; Charles J Vecht; Karima Mokhtari; Pieter Wesseling; Salvador Villa; Elizabeth Eisenhauer; Thierry Gorlia; Michael Weller; Denis Lacombe; J Gregory Cairncross; René-Olivier Mirimanoff Journal: Lancet Oncol Date: 2009-03-09 Impact factor: 41.316
Authors: Jeanette E Eckel-Passow; Daniel H Lachance; Annette M Molinaro; Kyle M Walsh; Paul A Decker; Hugues Sicotte; Melike Pekmezci; Terri Rice; Matt L Kosel; Ivan V Smirnov; Gobinda Sarkar; Alissa A Caron; Thomas M Kollmeyer; Corinne E Praska; Anisha R Chada; Chandralekha Halder; Helen M Hansen; Lucie S McCoy; Paige M Bracci; Roxanne Marshall; Shichun Zheng; Gerald F Reis; Alexander R Pico; Brian P O'Neill; Jan C Buckner; Caterina Giannini; Jason T Huse; Arie Perry; Tarik Tihan; Mitchell S Berger; Susan M Chang; Michael D Prados; Joseph Wiemels; John K Wiencke; Margaret R Wrensch; Robert B Jenkins Journal: N Engl J Med Date: 2015-06-10 Impact factor: 176.079
Authors: Yuchen Jiao; Patrick J Killela; Zachary J Reitman; Ahmed B Rasheed; Christopher M Heaphy; Roeland F de Wilde; Fausto J Rodriguez; Sergio Rosemberg; Sueli Mieko Oba-Shinjo; Suely Kazue Nagahashi Marie; Chetan Bettegowda; Nishant Agrawal; Eric Lipp; Christopher Pirozzi; Giselle Lopez; Yiping He; Henry Friedman; Allan H Friedman; Gregory J Riggins; Matthias Holdhoff; Peter Burger; Roger McLendon; Darell D Bigner; Bert Vogelstein; Alan K Meeker; Kenneth W Kinzler; Nickolas Papadopoulos; Luis A Diaz; Hai Yan Journal: Oncotarget Date: 2012-07
Authors: Hai Yan; D Williams Parsons; Genglin Jin; Roger McLendon; B Ahmed Rasheed; Weishi Yuan; Ivan Kos; Ines Batinic-Haberle; Siân Jones; Gregory J Riggins; Henry Friedman; Allan Friedman; David Reardon; James Herndon; Kenneth W Kinzler; Victor E Velculescu; Bert Vogelstein; Darell D Bigner Journal: N Engl J Med Date: 2009-02-19 Impact factor: 176.079