title: Genetic and epigenetic stability of oligodendrogliomas at recurrence.
abstract: Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression.
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.|Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
authors.forename: Koki
authors.initials: K
authors.lastname: Aihara
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan. mukasa-nsu@umin.ac.jp.
authors.forename: Akitake
authors.identifier: 0000-0001-7776-9086
authors.initials: A
authors.lastname: Mukasa
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
authors.forename: Genta
authors.initials: G
authors.lastname: Nagae
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Nomura
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tatsuno
authors.affiliation: Department of Pathology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Shibahara
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Miwako
authors.initials: M
authors.lastname: Takahashi
authors.affiliation: Division of Nuclear Medicine, Department of Radiology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Momose
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Shota
authors.initials: S
authors.lastname: Tanaka
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Shunsaku
authors.initials: S
authors.lastname: Takayanagi
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Yanagisawa
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Takahide
authors.initials: T
authors.lastname: Nejo
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takahashi
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Omata
authors.affiliation: Department of Neurosurgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Otani
authors.affiliation: Department of Neurosurgery, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka-City, Tokyo, 181-8611, Japan.
authors.forename: Kuniaki
authors.initials: K
authors.lastname: Saito
authors.affiliation: Department of Neurosurgery and Neuro-Oncology, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan.
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Narita
authors.affiliation: Department of Neurosurgery, Kyorin University Faculty of Medicine, 6-20-2 Shinkawa, Mitaka-City, Tokyo, 181-8611, Japan.
authors.forename: Motoo
authors.initials: M
authors.lastname: Nagane
authors.affiliation: Department of Neuro-Oncology/Neurosurgery, Saitama International Medical Center, Saitama Medical University, 1397-1 Yamane, Hidaka-shi, Saitama, 350-1298, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nishikawa
authors.affiliation: Department of Neurosurgery, Dokkyo Medical University, 880 Kitakobayashi, Mibu-machi, Shimotsuga-gun, Tochigi, 321-0293, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Ueki
authors.affiliation: Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan. haburata-tky@umin.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: Department of Neurosurgery, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-8655, Japan.
authors.forename: Nobuhito
authors.initials: N
authors.lastname: Saito
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D015331:Cohort Studies; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009837:Oligodendroglioma / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor
keywords: Heterogeneity; Hypermutator; Methylation; Mutation; Oligodendroglioma