title: Transcriptional diversity of long-term glioblastoma survivors.
abstract: BACKGROUND
  Glioblastoma (GBM) is a highly aggressive type of glioma with poor prognosis. However, a small number of patients live much longer than the median survival. A better understanding of these long-term survivors (LTSs) may provide important insight into the biology of GBM.
  
  
  METHODS
  We identified 7 patients with GBM, treated at Memorial Sloan-Kettering Cancer Center (MSKCC), with survival >48 months. We characterized the transcriptome of each patient and determined rates of MGMT promoter methylation and IDH1 and IDH2 mutational status. We identified LTSs in 2 independent cohorts (The Cancer Genome Atlas [TCGA] and NCI Repository for Molecular Brain Neoplasia Data [REMBRANDT]) and analyzed the transcriptomal characteristics of these LTSs.
  
  
  RESULTS
  The median overall survival of our cohort was 62.5 months. LTSs were distributed between the proneural (n = 2), neural (n = 2), classical (n = 2), and mesenchymal (n = 1) subtypes. Similarly, LTS in the TCGA and REMBRANDT cohorts demonstrated diverse transcriptomal subclassification identities. The majority of the MSKCC LTSs (71%) were found to have methylation of the MGMT promoter. None of the patients had an IDH1 or IDH2 mutation, and IDH mutation occurred in a minority of the TCGA LTSs as well. A set of 60 genes was found to be differentially expressed in the MSKCC and TCGA LTSs.
  
  
  CONCLUSIONS
  While IDH mutant proneural tumors impart a better prognosis in the short-term, survival beyond 4 years does not require IDH mutation and is not dictated by a single transcriptional subclass. In contrast, MGMT methylation continues to have strong prognostic value for survival beyond 4 years. These findings have substantial impact for understanding GBM biology and progression.
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Naamit K
authors.initials: NK
authors.lastname: Gerber
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Anuj
authors.initials: A
authors.lastname: Goenka
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Sevin
authors.initials: S
authors.lastname: Turcan
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Marsha
authors.initials: M
authors.lastname: Reyngold
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Vladimir
authors.initials: V
authors.lastname: Makarov
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Kasthuri
authors.initials: K
authors.lastname: Kannan
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Kathryn
authors.initials: K
authors.lastname: Beal
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Antonio
authors.initials: A
authors.lastname: Omuro
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Yamada
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Phillip
authors.initials: P
authors.lastname: Gutin
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Cameron W
authors.initials: CW
authors.lastname: Brennan
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.affiliation: Department of Radiation Oncology, Memorial Sloan-Kettering Cancer Center, New York, New York (N.K.G., A.G., M.R., K.B., Y.Y., T.A.C.); Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, New York (S.T., V.M., K.K., T.A.C.); Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, New York (A.O.); Department of Neurosurgery, Memorial Sloan-Kettering Cancer Center, New York, New York (P.G., C.W.B.); Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York (J.T.H.).
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Chan
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000235:genetics* / Q000401:mortality*; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics*; D004252:DNA Mutational Analysis; D045643:DNA Repair Enzymes / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000235:genetics* / Q000401:mortality*; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D017741:Survivors; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D025521:Tumor Suppressor Proteins; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes
keywords: TCGA; gene expression; glioblastoma; prognostic genes