title: Epigenetic subclassification of meningiomas based on genome-wide DNA methylation analyses.
abstract: Meningiomas are among the most common intracranial tumors and are mostly curable by surgical resection. However, some populations of meningiomas with benign histological profiles show malignant behavior. The reasons for this inconsistency are yet to be ascertained, and novel diagnostic criteria other than the histological one are urgently needed. The aim of the present study is to subclassify meningiomas from the viewpoint of gene methylation and to determine the subgroup with malignant characteristics. Thirty meningiomas were analyzed using microarrays for 6157 genes and were classified into three clusters on the basis of their methylation status; these were found to be independent of the histological grading. One of the clusters showed a high frequency of recurrence, with a marked accumulation of methylation in a subset of genes. We hypothesized that the aggressive meningiomas universally share characteristic methylation in certain genes; therefore, we chose the genes that strongly contributed to cluster formation. The quantified methylation values of five chosen genes (HOXA6, HOXA9, PENK, UPK3A and IGF2BP1) agreed well with microarray findings, and a scoring system consisting of the five genes significantly correlated with a high frequency of recurrence in an additional validation set of 32 patients. Of particular note is that three cases with malignant transformation already showed hypermethylation at histologically benign stage. In conclusion, a subgroup of meningiomas is characterized by aberrant hypermethylation of the subset of genes in the early stage of tumorigenesis, and our findings highlight the possibility of speculating potential malignancy of meningiomas by assessing methylation status.
authors.affiliation: Department of Neurosurgery, Nagoya University School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, Aichi 466-8550, Japan.
authors.forename: Yugo
authors.initials: Y
authors.lastname: Kishida
authors.forename: Atsushi
authors.initials: A
authors.lastname: Natsume
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Kondo
authors.forename: Ichiro
authors.initials: I
authors.lastname: Takeuchi
authors.forename: Byonggu
authors.initials: B
authors.lastname: An
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Okamoto
authors.forename: Keiko
authors.initials: K
authors.lastname: Shinjo
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Saito
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Ando
authors.forename: Fumiharu
authors.initials: F
authors.lastname: Ohka
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Sekido
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Wakabayashi
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D018450:Disease Progression; D057890:Epigenomics / Q000379:methods; D005260:Female; D005500:Follow-Up Studies; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D008577:Meningeal Neoplasms / Q000145:classification* / Q000235:genetics / Q000473:pathology; D008579:Meningioma / Q000145:classification* / Q000235:genetics / Q000473:pathology; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D012189:Retrospective Studies