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

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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 (≥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.

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Acknowledgments

This study was supported by grants from Cancer Research UK (Grant C8464/A5497; to S. C. Clifford and D.W. Ellison), The Katie Trust (to S.C. Clifford), and the Samantha Dickson Brain Tumour Research Trust (to S.C. Clifford). Medulloblastomas investigated in this study include samples provided by the UK Children’s Cancer and Leukaemia Group (CCLG) as part of CCLG-approved biological study BS-2007-04. This study was conducted with Ethics Committee approval from Newcastle/North Tyneside REC (study reference 07/Q0905/71). Cell lines MHH-MED-1 and MHH-MED-8A were kind gifts from Prof. T. Pietsch, University of Bonn Medical Centre, Germany. D458MED cells were kindly provided by Prof. D. Bigner, Duke University, USA. IMR-32 cells were provided by Dr. D. Tweddle, Newcastle University, UK. Cell lines D341Med and D384 Med were obtained from the American Type Culture Collection.

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Correspondence to Steven C. Clifford.

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Ryan, S.L., Schwalbe, E.C., Cole, M. et al. MYC family amplification and clinical risk-factors interact to predict an extremely poor prognosis in childhood medulloblastoma. Acta Neuropathol 123, 501–513 (2012). https://doi.org/10.1007/s00401-011-0923-y

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  • DOI: https://doi.org/10.1007/s00401-011-0923-y

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