title: Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma.
abstract: Meningioma is the most common primary brain tumor and carries a substantial risk of local recurrence. Methylation profiles of meningioma and their clinical implications are not well understood. We hypothesized that aggressive meningiomas have unique DNA methylation patterns that could be used to better stratify patient management. Samples (n = 140) were profiled using the Illumina HumanMethylation450BeadChip. Unsupervised modeling on a training set (n = 89) identified 2 molecular methylation subgroups of meningioma (MM) with significantly different recurrence-free survival (RFS) times between the groups: a prognostically unfavorable subgroup (MM-UNFAV) and a prognostically favorable subgroup (MM-FAV). This finding was validated in the remaining 51 samples and led to a baseline meningioma methylation classifier (bMMC) defined by 283 CpG loci (283-bMMC). To further optimize a recurrence predictor, probes subsumed within the baseline classifier were subject to additional modeling using a similar training/validation approach, leading to a 64-CpG loci meningioma methylation predictor (64-MMP). After adjustment for relevant clinical variables [WHO grade, mitotic index, Simpson grade, sex, location, and copy number aberrations (CNAs)] multivariable analyses for RFS showed that the baseline methylation classifier was not significant (p = 0.0793). The methylation predictor, however, was significantly associated with tumor recurrence (p < 0.0001). CNAs were extracted from the 450k intensity profiles. Tumor samples in the MM-UNFAV subgroup showed an overall higher proportion of CNAs compared to the MM-FAV subgroup tumors and the CNAs were complex in nature. CNAs in the MM-UNFAV subgroup included recurrent losses of 1p, 6q, 14q and 18q, and gain of 1q, all of which were previously identified as indicators of poor outcome. In conclusion, our analyses demonstrate robust DNA methylation signatures in meningioma that correlate with CNAs and stratify patients by recurrence risk.
authors.affiliation: Departments of Pathology and Laboratory Medicine and Neurosurgery, Medical University of South Carolina and Hollings Cancer Center, 171 Ashley Ave., MSC 908, Charleston, SC, 29425, USA. adriana_olar@yahoo.com.
authors.forename: Adriana
authors.identifier: 0000-0001-7119-7654
authors.initials: A
authors.lastname: Olar
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 2130 W Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Khalida M
authors.initials: KM
authors.lastname: Wani
authors.affiliation: Center for Nursing Research, The University of Texas School of Nursing, 6901 Bertner St., Houston, TX, 77030, USA.
authors.forename: Charmaine D
authors.initials: CD
authors.lastname: Wilson
authors.affiliation: Princess Margaret Cancer Centre, MacFeeters-Hamilton Brain Tumour Centre, College Street 101, Toronto, M5G 1L7, ON, Canada.
authors.forename: Gelareh
authors.initials: G
authors.lastname: Zadeh
authors.affiliation: Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Franco
authors.initials: F
authors.lastname: DeMonte
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Network (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.
authors.forename: David T W
authors.initials: DT
authors.lastname: Jones
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), German Cancer Network (DKTK), Im Neuenheimer Feld 280, 69120, Heidelberg, Germany.|Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Im Neuenheimer Feld 430, 69120, Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, 2130 W Holcombe Blvd., Houston, TX, 77030, USA.|Departments of Radiation Oncology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX, 77030, USA.
authors.forename: Erik P
authors.initials: EP
authors.lastname: Sulman
authors.affiliation: Princess Margaret Cancer Centre, MacFeeters-Hamilton Brain Tumour Centre, College Street 101, Toronto, M5G 1L7, ON, Canada.
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D056915:DNA Copy Number Variations / Q000235:genetics; D019175:DNA Methylation / Q000502:physiology*; D018572:Disease-Free Survival; D057890:Epigenomics / Q000379:methods*; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D019394:Ki-67 Antigen / Q000378:metabolism; D008297:Male; D008577:Meningeal Neoplasms / Q000401:mortality*; D008579:Meningioma / Q000401:mortality*; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000401:mortality*; D018709:Statistics, Nonparametric; D055815:Young Adult
chemical_list: D019394:Ki-67 Antigen
keywords: Copy number aberrations; DNA methylation; Epigenetics; Meningioma; Molecular subgroups; Recurrence risk