title: Clonal selection drives genetic divergence of metastatic medulloblastoma.
abstract: Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Center, Program in Developmental and Stem Cell Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
authors.forename: Xiaochong
authors.initials: X
authors.lastname: Wu
authors.forename: Paul A
authors.initials: PA
authors.lastname: Northcott
authors.forename: Adrian
authors.initials: A
authors.lastname: Dubuc
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Dupuy
authors.forename: David J H
authors.initials: DJ
authors.lastname: Shih
authors.forename: Hendrik
authors.initials: H
authors.lastname: Witt
authors.forename: Sidney
authors.initials: S
authors.lastname: Croul
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.forename: Daniel W
authors.initials: DW
authors.lastname: Fults
authors.forename: Charles G
authors.initials: CG
authors.lastname: Eberhart
authors.forename: Livia
authors.initials: L
authors.lastname: Garzia
authors.forename: Timothy
authors.initials: T
authors.lastname: Van Meter
authors.forename: David
authors.initials: D
authors.lastname: Zagzag
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.forename: Jeremy
authors.initials: J
authors.lastname: Schwartzentruber
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Todd E
authors.initials: TE
authors.lastname: Scheetz
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Xiao-Nan
authors.initials: XN
authors.lastname: Li
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Scherer
authors.forename: Yoon-Jae
authors.initials: YJ
authors.lastname: Cho
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.forename: Tobey J
authors.initials: TJ
authors.lastname: MacDonald
authors.forename: Jan
authors.initials: J
authors.lastname: Koster
authors.forename: Martin G
authors.initials: MG
authors.lastname: McCabe
authors.forename: Aaron L
authors.initials: AL
authors.lastname: Sarver
authors.forename: V Peter
authors.initials: VP
authors.lastname: Collins
authors.forename: William A
authors.initials: WA
authors.lastname: Weiss
authors.forename: David A
authors.initials: DA
authors.lastname: Largaespada
authors.forename: Lara S
authors.initials: LS
authors.lastname: Collier
authors.forename: Michael D
authors.initials: MD
authors.lastname: Taylor
mesh_terms: D000818:Animals; D060965:Clonal Evolution / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation; D004251:DNA Transposable Elements / Q000235:genetics; D004195:Disease Models, Animal; D016158:Genes, p53 / Q000235:genetics; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000150:complications / Q000235:genetics; D008527:Medulloblastoma / Q000150:complications / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D016254:Mutagenesis, Insertional; D009362:Neoplasm Metastasis / Q000235:genetics* / Q000473:pathology*; D015996:Survival Rate
chemical_list: D004251:DNA Transposable Elements