Molecular stratification of medulloblastoma: comparison of histological and genetic methods to detect Wnt activated tumours
Version of Record online: 29 JAN 2015
© 2014 British Neuropathological Society
Neuropathology and Applied Neurobiology
Volume 41, Issue 2, pages 135–144, February 2015
How to Cite
Goschzik, T., zur Mühlen, A., Kristiansen, G., Haberler, C., Stefanits, H., Friedrich, C., von Hoff, K., Rutkowski, S., Pfister, S. M. and Pietsch, T. (2015), Molecular stratification of medulloblastoma: comparison of histological and genetic methods to detect Wnt activated tumours. Neuropathology and Applied Neurobiology, 41: 135–144. doi: 10.1111/nan.12161
- Issue online: 29 JAN 2015
- Version of Record online: 29 JAN 2015
- Accepted manuscript online: 4 JUN 2014 05:37AM EST
- Manuscript Accepted: 30 MAY 2014
- Manuscript Received: 12 DEC 2013
- German Federal Ministry of Education and Research (BMBF. Grant Number: 01ES0806
- German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung)
- Oesterreichische Nationalbank. Grant Number: 13648
- mutation analysis;
- Wnt signalling
Wnt activation in medulloblastomas is associated with good outcome. Upfront testing and risk-adapted stratification of patients will be done in future clinical studies. In a cohort of 186 paediatric medulloblastomas our aim was to identify the optimal methods in standard clinical practice to detect this subgroup.
Nuclear accumulation of β-catenin was analysed by immunohistochemistry (IHC). DNA of FFPE tissue was amplified by PCR for single-strand conformation polymorphism analysis and direct sequencing of CTNNB1 exon 3. Copy number of chromosome 6 was analysed by multiplex ligation-dependent probe amplification and molecular inversion profiling.
Different automated immunostaining systems showed similar results. Twenty-one of 186 samples had nuclear accumulation in ≥5% of cells, 17 samples showed <5% β-catenin positive nuclei. None of these 17 cases had CTNNB1 mutations, but 18 of 21 cases with ≥5% accumulation did, identifying these 18 cases as Wnt-subgroup medulloblastomas. Fifteen of 18 mutated cases showed monosomy 6, 3 had balanced chromosome 6. On the contrary, none of the CTNNB1 wild-type tumours had monosomy 6.
Standard neuropathological evaluation of medulloblastoma samples should include IHC of β-catenin because tumours with high nuclear accumulation of β-catenin most probably belong to the Wnt subgroup of medulloblastomas. Still, IHC alone may be insufficient to detect all Wnt cases. Similarly, chromosome 6 aberrations were not present in all CTNNB1-mutated cases. Therefore, we conclude that sequencing analysis of CTNNB1 exon 3 in combination with β-catenin IHC (possibly as pre-screening method) is a feasible and cost-efficient way for the determination of Wnt medulloblastomas.