title: Epigenetic suppression of EGFR signaling in G-CIMP+ glioblastomas.
abstract: The intrinsic signaling cascades and cell states associated with the Glioma CpG Island Methylator Phenotype (G-CIMP) remain poorly understood. Using published mRNA signatures associated with EGFR activation, we demonstrate that G-CIMP+ tumors harbor decreased EGFR signaling using three independent datasets, including the Chinese Glioma Genome Atlas(CGGA; n=155), the REMBRANDT dataset (n=288), and The Cancer Genome Atlas (TCGA; n=406). Additionally, an independent collection of 25 fresh-frozen glioblastomas confirmed lowered pERK levels in G-CIMP+ specimens (p<0.001), indicating suppressed EGFR signaling. Analysis of TCGA glioblastomas revealed that G-CIMP+ glioblastomas harbored lowered mRNA levels for EGFR and H-Ras. Induction of G-CIMP+ state by exogenous expression of a mutated isocitrate dehydrogenase 1, IDH1-R132H, suppressed EGFR and H-Ras protein expression as well as pERK accumulation in independent glioblastoma models. These suppressions were associated with increased deposition of the repressive histone markers, H3K9me3 and H3K27me3, in the EGFR and H-Ras promoter regions. The IDH1-R132H expression-induced pERK suppression can be reversed by exogenous expression of H-RasG12V. Finally, the G-CIMP+ Ink4a-Arf-/- EGFRvIII glioblastoma line was more resistant to the EGFR inhibitor, Gefitinib, relative to its isogenic G-CIMP- counterpart. These results suggest that G-CIMP epigenetically regulates EGFR signaling and serves as a predictive biomarker for EGFR inhibitors in glioblastoma patients.
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego. Contributed equally to this work.
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego. Contributed equally to this work.
authors.forename: Zachary J
authors.initials: ZJ
authors.lastname: Taich
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego.
authors.forename: Amit
authors.initials: A
authors.lastname: Goyal
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego.
authors.forename: David
authors.initials: D
authors.lastname: Gonda
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego.
authors.forename: Johnny
authors.initials: J
authors.lastname: Akers
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego.
authors.forename: Bandita
authors.initials: B
authors.lastname: Adhikari
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego.
authors.forename: Kunal
authors.initials: K
authors.lastname: Patel
authors.affiliation: Department of Pathology, University of California, San Diego.
authors.forename: Scott
authors.initials: S
authors.lastname: Vandenberg
authors.affiliation: Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Bao
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego.
authors.forename: Bob S
authors.initials: BS
authors.lastname: Carter
authors.affiliation: Department of Neurosurgery, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Renzhi
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Mao
authors.affiliation: Department of Neurosurgery, Tiantan Hospital, Capital Medical University, Beijing, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Jiang
authors.affiliation: Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, University of California, San Diego.
authors.forename: Clark C
authors.initials: CC
authors.lastname: Chen
mesh_terms: D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism; D047369:Chromatin Immunoprecipitation; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D044127:Epigenesis, Genetic / Q000502:physiology*; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D010641:Phenotype; D016133:Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D059467:Transcriptome; D014162:Transfection
chemical_list: C512478:EGFR protein, human; D066246:ErbB Receptors