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Acta Neuropathologica

, Volume 123, Issue 4, pp 501–513 | Cite as

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

  • Sarra L. Ryan
  • Ed C. Schwalbe
  • Michael Cole
  • Yuan Lu
  • Meryl E. Lusher
  • Hisham Megahed
  • Kieran O’Toole
  • Sarah Leigh Nicholson
  • Laszlo Bognar
  • Miklos Garami
  • Peter Hauser
  • Andrey Korshunov
  • Stefan M. Pfister
  • Daniel Williamson
  • Roger E. Taylor
  • David W. Ellison
  • Simon Bailey
  • Steven C. CliffordEmail author
Original Paper

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.

Keywords

MYC MYCN Medulloblastoma Biomarkers Prognosis 

Notes

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.

Supplementary material

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Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Sarra L. Ryan
    • 1
  • Ed C. Schwalbe
    • 1
  • Michael Cole
    • 1
  • Yuan Lu
    • 1
  • Meryl E. Lusher
    • 1
  • Hisham Megahed
    • 1
  • Kieran O’Toole
    • 1
  • Sarah Leigh Nicholson
    • 1
  • Laszlo Bognar
    • 2
  • Miklos Garami
    • 3
  • Peter Hauser
    • 3
  • Andrey Korshunov
    • 4
  • Stefan M. Pfister
    • 4
  • Daniel Williamson
    • 1
  • Roger E. Taylor
    • 5
  • David W. Ellison
    • 6
  • Simon Bailey
    • 1
  • Steven C. Clifford
    • 1
    Email author
  1. 1.Northern Institute for Cancer ResearchNewcastle University, Sir James Spence Institute Level 5, Royal Victoria InfirmaryNewcastle upon TyneUK
  2. 2.Department of NeurosurgeryUniversity of DebrecenDebrecenHungary
  3. 3.Department of PaediatricsSemmelweis UniversityBudapestHungary
  4. 4.German Cancer Research Center, University Hospital HeidelbergHeidelbergGermany
  5. 5.South Wales Cancer Centre, Singleton HospitalSwanseaUK
  6. 6.Department of PathologySt. Jude Children’s Research HospitalMemphisUSA

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