title: Activation of the NRF2 pathway and its impact on the prognosis of anaplastic glioma patients.
abstract: BACKGROUND
  Nuclear factor erythroid 2-related factor 2 (NRF2) plays pivotal roles in cytoprotection. We aimed at clarifying the contribution of the NRF2 pathway to malignant glioma pathology.
  
  
  METHODS
  NRF2 target gene expression and its association with prognosis were examined in 95 anaplastic gliomas with or without isocitrate dehydrogenase (IDH) 1/2 gene mutations and 52 glioblastomas. To explore mechanisms for the altered activity of the NRF2 pathway, we examined somatic mutations and expressions of the NRF2 gene and those encoding NRF2 regulators, Kelch-like ECH-associated protein 1 (KEAP1) and p62/SQSTSM. To clarify the functional interaction between IDH1 mutations and the NRF2 pathway, we introduced a mutant IDH1 to T98 glioblastoma-derived cells and examined the NRF2 activity in these cells.
  
  
  RESULTS
  NRF2 target genes were elevated in 13.7% and 32.7% of anaplastic gliomas and glioblastomas, respectively. Upregulation of NRF2 target genes correlated with poor prognosis in anaplastic gliomas but not in glioblastomas. Neither somatic mutations of NRF2/KEAP1 nor dysregulated expression of KEAP1/p62 explained the increased expression of NRF2 target genes. In most cases of anaplastic glioma with mutated IDH1/2, NRF2 and its target genes were downregulated. This was reproducible in IDH1 R132H-expressing T98 cells. In minor cases of IDH1/2-mutant anaplastic gliomas with increased expression of NRF2 target genes, the clinical outcomes were significantly poor.
  
  
  CONCLUSIONS
  The NRF2 activity is increased in a significant proportion of malignant gliomas in general but decreased in the majority of IDH1/2-mutant anaplastic gliomas. It is plausible that the NRF2 pathway plays an important role in tumor progression of anaplastic gliomas with IDH1/2 mutations.
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Masayuki
authors.initials: M
authors.lastname: Kanamori
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Higa
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Yukihiko
authors.initials: Y
authors.lastname: Sonoda
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Shohei
authors.initials: S
authors.lastname: Murakami
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Mina
authors.initials: M
authors.lastname: Dodo
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kitamura
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Keiko
authors.initials: K
authors.lastname: Taguchi
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Tatsuhiro
authors.initials: T
authors.lastname: Shibata
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Mika
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Hiroyoshi
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Ichiyo
authors.initials: I
authors.lastname: Shibahara
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Ryuta
authors.initials: R
authors.lastname: Saito
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Yoji
authors.initials: Y
authors.lastname: Yamashita
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Kumabe
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamamoto
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Hozumi
authors.initials: H
authors.lastname: Motohashi
authors.affiliation: Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (M.K., Y.S., I.S., R.S., T.K., T.T.); Department of Gene Expression Regulation, Institute of Development, Aging, and Cancer, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H., S.M., M.D., H.K., K.T., H.M.); Center for Radioisotope Sciences, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (T.H.); Department of Medical Biochemistry, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan (S.M., K.T., M.Y.); Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan (T.S.); Department of Pathology, Tohoku University Hospital, Sendai, Miyagi, Japan (M.W.); Department of Pathology and Laboratory Medicine, Sendai Medical Center, Sendai, Miyagi, Japan (H.S.); Department of Neurosurgery, Miyagi Cancer Center, Natori, Miyagi, Japan (Y.Y.).
authors.forename: Teiji
authors.initials: T
authors.lastname: Tominaga
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001932:Brain Neoplasms / Q000175:diagnosis* / Q000378:metabolism*; D002648:Child; D005260:Female; D015870:Gene Expression; D005909:Glioblastoma / Q000175:diagnosis / Q000378:metabolism; D005910:Glioma / Q000175:diagnosis* / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007521:Isocitrate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000072019:Kelch-Like ECH-Associated Protein 1; D008297:Male; D008875:Middle Aged; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000235:genetics*; D011379:Prognosis; D016601:RNA-Binding Proteins / Q000378:metabolism; D015398:Signal Transduction; D055815:Young Adult
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; C118585:P62 protein, human; D016601:RNA-Binding Proteins; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human
keywords: IDH1/2 gene; Keap1-NRF2 system; malignant glioma; prognosis