title: MYC family amplification and clinical risk-factors interact to predict an extremely poor prognosis in childhood medulloblastoma.
abstract: The MYC oncogenes are the most commonly amplified loci in medulloblastoma, and have previously been proposed as biomarkers of adverse disease prognosis by us and others. Here, we report focussed and comprehensive investigations of MYCC, MYCN and MYCL in an extensive medulloblastoma cohort (n = 292), aimed to define more precisely their biological significance and optimal clinical application to direct improved disease risk-stratification and individualisation of therapy. MYCC and MYCN expression elevations were multifactorial, associated with high-risk (gene amplification, large-cell/anaplastic pathology (LCA)) and favourable-risk (WNT/SHH molecular subgroups) disease features. Highly variable cellular gene amplification patterns underlay overall MYC copy number elevations observed in tumour biopsies; we used these alternative measures together to define quantitative methodologies and thresholds for amplification detection in routinely collected tumour material. MYCC and MYCN amplification, but not gain, each had independent prognostic significance in non-infants (≥3.0-16.0 years), but MYCC conferred a greater hazard to survival than MYCN when considered across this treatment group. MYCN's weaker group-wide survival relationship may be explained by its pleiotropic behaviour between clinical disease-risk groups; MYCN predicted poor prognosis in clinical high-risk (metastatic (M+) or LCA), but not standard-risk, patients. Extending these findings, survival decreased in proportion to the total number of independently significant high-risk features present (LCA, M+ or MYCC/MYCN amplification). This cumulative-risk model defines a patient group characterised by ≥2 independent risk-factors and an extremely poor prognosis (<15% survival), which can be identified straightforwardly using the reported MYC amplification detection methodologies alongside clinical assessments, enabling targeting for novel/intensified therapies in future clinical studies.
authors.affiliation: Northern Institute for Cancer Research, Newcastle University, Sir James Spence Institute Level, Royal Victoria Infirmary, Newcastle upon Tyne, UK.
authors.forename: Sarra L
authors.initials: SL
authors.lastname: Ryan
authors.forename: Ed C
authors.initials: EC
authors.lastname: Schwalbe
authors.forename: Michael
authors.initials: M
authors.lastname: Cole
authors.forename: Yuan
authors.initials: Y
authors.lastname: Lu
authors.forename: Meryl E
authors.initials: ME
authors.lastname: Lusher
authors.forename: Hisham
authors.initials: H
authors.lastname: Megahed
authors.forename: Kieran
authors.initials: K
authors.lastname: O'Toole
authors.forename: Sarah Leigh
authors.initials: SL
authors.lastname: Nicholson
authors.forename: Laszlo
authors.initials: L
authors.lastname: Bognar
authors.forename: Miklos
authors.initials: M
authors.lastname: Garami
authors.forename: Peter
authors.initials: P
authors.lastname: Hauser
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.forename: Daniel
authors.initials: D
authors.lastname: Williamson
authors.forename: Roger E
authors.initials: RE
authors.lastname: Taylor
authors.forename: David W
authors.initials: DW
authors.lastname: Ellison
authors.forename: Simon
authors.initials: S
authors.lastname: Bailey
authors.forename: Steven C
authors.initials: SC
authors.lastname: Clifford
mesh_terms: D000293:Adolescent; D002528:Cerebellar Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D056915:DNA Copy Number Variations / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D006801:Humans; D008297:Male; D008527:Medulloblastoma / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011237:Predictive Value of Tests; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012307:Risk Factors; D016019:Survival Analysis; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C116115:MYCBP protein, human; C459801:MYCN protein, human; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D014157:Transcription Factors