Toggle Main Menu Toggle Search

Open Access padlockePrints

Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial

Lookup NU author(s): Professor Steven Clifford, Dr Ed Schwalbe, Dr Debbie Hicks, Kieran O'Toole, Sarah Nicholson

Downloads

Full text for this publication is not currently held within this repository. Alternative links are provided below where available.


Abstract

PURPOSE: To improve stratification of risk-adapted treatment for non-metastatic(M0), standard-risk medulloblastoma patients by prospective evaluation ofbiomarkers of reported biological or prognostic significance, alongsideclinico-pathological variables, within the multi-center HIT-SIOP-PNET4 trial.METHODS: Formalin-fixed paraffin-embedded tumor tissues were collected from 338M0 patients (>4.0 years at diagnosis) for pathology review and assessment of the WNT subgroup (MBWNT) and genomic copy-number defects (chromosome 17, MYC/MYCN,9q22 (PTCH1) and DNA ploidy). Clinical characteristics were reviewed centrally.RESULTS: The favorable prognosis of MBWNT was confirmed, however better outcomes were observed for non-MBWNT tumors in this clinical risk-defined cohort compared to previous disease-wide clinical trials. Chromosome 17p/q defects wereheterogeneous when assessed at the cellular copy-number level, and predicted poorprognosis when they occurred against a diploid (ch17(im)/diploid(cen)), but notpolyploid, genetic background. These factors, together with post-surgical tumorresiduum (R+) and radiotherapy delay, were supported as independent prognosticmarkers in multivariate testing. Notably, MYC and MYCN amplification were notassociated with adverse outcome. In cross-validated survival models derived forthe clinical standard-risk (M0/R0) disease group, (ch17(im)/diploid(cen); 14% of patients) predicted high disease-risk, while the outcomes of patients without(ch17(im)/diploid(cen)) did not differ significantly from MBWNT, allowingre-classification of 86% as favorable-risk.CONCLUSIONS: Biomarkers, established previously in disease-wide studies, behavedifferently in clinically-defined standard-risk disease. Distinct biomarkers are required to assess disease-risk in this group, and define improvedrisk-stratification models. Routine testing for specific patterns of chromosome17 imbalance at the cellular level, and MBWNT, provides a strong basis forincorporation into future trials.


Publication metadata

Author(s): Clifford SC, Lannering B, Schwalbe EC, Hicks D, O'Toole K, Nicholson SL, Goschzik T, Zur-Mühlen A, Figarella-Branger D, Doz F, Rutkowski S, Gustafsson G, Pietsch T

Publication type: Article

Publication status: Published

Journal: Oncotarget

Year: 2015

Volume: 6

Issue: 36

Pages: 38827-38839

Online publication date: 05/09/2015

Acceptance date: 24/08/2015

ISSN (electronic): 1949-2553

Publisher: Impact Journals

URL: http://dx.doi.org/10.18632/oncotarget.5149

DOI: 10.18632/oncotarget.5149

PubMed id: 26420814


Altmetrics

Altmetrics provided by Altmetric


Actions

Find at Newcastle University icon    Link to this publication


Share