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MYC family amplification and clinical risk-factors interact to predict an extremely poor prognosis in childhood medulloblastoma

Lookup NU author(s): Dr Sarra Ryan, Dr Ed Schwalbe, Mike Cole, Yuan Lu, Dr Meryl Lusher, Dr Hisham Megahed, Kieran O'Toole, Dr Daniel Williamson, Professor David Ellison, Professor Simon Bailey, Professor Steven Clifford

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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 (a parts per thousand yen3.0-16.0 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 a parts per thousand yen2 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.


Publication metadata

Author(s): Ryan SL, Schwalbe EC, Cole M, Lu Y, Lusher ME, Megahed H, O'Toole K, Nicholson SL, Bognar L, Garami M, Hauser P, Korshunov A, Pfister SM, Williamson D, Taylor RE, Ellison DW, Bailey S, Clifford SC

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica

Year: 2012

Volume: 123

Issue: 4

Pages: 501-513

Print publication date: 01/04/2012

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer

URL: http://dx.doi.org/10.1007/s00401-011-0923-y

DOI: 10.1007/s00401-011-0923-y


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