Genetic, epigenetic, and molecular landscapes of multifocal and multicentric glioblastoma.
Ten to twenty percent of newly diagnosed glioblastoma (GBM) patients initially present with multiple lesions, termed multifocal or multicentric GBM (M-GBM). The prognosis of these patients is poorer than that of solitary GBM (S-GBM) patients. However, it is unknown whether multifocality has a genetic, epigenetic, or molecular basis. Here, we identified the genetic and epigenetic characteristics of M-GBM by performing a comprehensive analysis of multidimensional data, including imaging, genetic, epigenetic, and gene expression profiles, from 30 M-GBM cases in The Cancer Genome Atlas database and comparing the results with those of 173 S-GBM cases. We found that M-GBMs had no IDH1, ATRX, or PDGFRA mutations and were significantly associated with the mesenchymal subtype. We also identified the CYB5R2 gene to be hypo-methylated and overexpressed in M-GBMs. The expression level of CYB5R2 was significantly associated with patient survival in two major independent GBM cohorts, totaling 758 cases. The IDH1 mutation was markedly associated with CYB5R2 promoter methylation, but the survival influence of CYB5R2 was independent of IDH1 mutation status. CYB5R2 expression was significantly associated with collagen maturation and the catabolic process and immunoregulation pathways. These results reveal that M-GBMs have some underlying genetic and epigenetic characteristics that are associated with poor prognosis and that CYB5R2 is a new epigenetic marker for GBM prognosis.
Department of Pathology, Unit 85, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.|Department of Neurosurgery, Key Laboratory of Cancer Prevention and Therapy of Tianjin, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Hospital and Institute, Tianjin, People's Republic of China.
Qun
Q
Liu
Department of Pathology, Unit 85, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
Yuexin
Y
Liu
Department of Neurosurgery, Key Laboratory of Cancer Prevention and Therapy of Tianjin, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Hospital and Institute, Tianjin, People's Republic of China.
Wenliang
W
Li
Department of Neurosurgery, Key Laboratory of Cancer Prevention and Therapy of Tianjin, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Hospital and Institute, Tianjin, People's Republic of China.
Xiaoguang
X
Wang
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Raymond
R
Sawaya
Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Frederick F
FF
Lang
Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
W K Alfred
WK
Yung
Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy of Tianjin, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Hospital and Institute, Tianjin, People's Republic of China.
Kexin
K
Chen
Department of Pathology, Unit 85, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
Gregory N
GN
Fuller
Department of Pathology, Unit 85, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA. wzhang@mdanderson.org.
Wei
W
Zhang
D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015331:Cohort Studies; D004265:DNA Helicases / Q000235:genetics; D019175:DNA Methylation; D016208:Databases, Factual; D044127:Epigenesis, Genetic; D005260:Female; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016019:Survival Analysis; D000075924:X-linked Nuclear Protein
D009687:Nuclear Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004265:DNA Helicases; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
Cytochrome b5 reductase 2; DNA methylation; Isocitrate dehydrogenase 1; Magnetic resonance imaging; Multicentric glioma; Multifocal glioma; Mutation