title: Medulloblastoma subgroups remain stable across primary and metastatic compartments.
abstract: Medulloblastoma comprises four distinct molecular variants with distinct genetics, transcriptomes, and outcomes. Subgroup affiliation has been previously shown to remain stable at the time of recurrence, which likely reflects their distinct cells of origin. However, a therapeutically relevant question that remains unanswered is subgroup stability in the metastatic compartment. We assembled a cohort of 12-paired primary-metastatic tumors collected in the MAGIC consortium, and established their molecular subgroup affiliation by performing integrative gene expression and DNA methylation analysis. Frozen tissues were collected and profiled using Affymetrix gene expression arrays and Illumina methylation arrays. Class prediction and hierarchical clustering were performed using existing published datasets. Our molecular analysis, using consensus integrative genomic data, establishes the unequivocal maintenance of molecular subgroup affiliation in metastatic medulloblastoma. We further validated these findings by interrogating a non-overlapping cohort of 19 pairs of primary-metastatic tumors from the Burdenko Neurosurgical Institute using an orthogonal technique of immunohistochemical staining. This investigation represents the largest reported primary-metastatic paired cohort profiled to date and provides a unique opportunity to evaluate subgroup-specific molecular aberrations within the metastatic compartment. Our findings further support the hypothesis that medulloblastoma subgroups arise from distinct cells of origin, which are carried forward from ontogeny to oncology.
authors.affiliation: Developmental and Stem Cell Biology Program, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.forename: Adrian M
authors.initials: AM
authors.lastname: Dubuc
authors.forename: Vijay
authors.initials: V
authors.lastname: Ramaswamy
authors.forename: Stephen
authors.initials: S
authors.lastname: Mack
authors.forename: Deena M A
authors.initials: DM
authors.lastname: Gendoo
authors.forename: Marc
authors.initials: M
authors.lastname: Remke
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Wu
authors.forename: Livia
authors.initials: L
authors.lastname: Garzia
authors.forename: Betty
authors.initials: B
authors.lastname: Luu
authors.forename: Florence
authors.initials: F
authors.lastname: Cavalli
authors.forename: John
authors.initials: J
authors.lastname: Peacock
authors.forename: Borja
authors.initials: B
authors.lastname: López
authors.forename: Patryk
authors.initials: P
authors.lastname: Skowron
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
authors.forename: David
authors.initials: D
authors.lastname: Lyden
authors.forename: Caitlin
authors.initials: C
authors.lastname: Hoffman
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.forename: Charles
authors.initials: C
authors.lastname: Eberhart
authors.forename: Tobey
authors.initials: T
authors.lastname: MacDonald
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.forename: Timothy
authors.initials: T
authors.lastname: Van Meter
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haibe-Kains
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.forename: James T
authors.initials: JT
authors.lastname: Rutka
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000293:Adolescent; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000473:pathology*; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D005260:Female; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000235:genetics* / Q000473:pathology*; D009362:Neoplasm Metastasis / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D059467:Transcriptome