Artikel
Genome-wide copy number analysis, neuropathological classification and analysis of hedgehog activation: Histology reflects genetics and biology in medulloblastomas of young children
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Autoren
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Elena Kapitza
- University of Bonn, Department of Neuropathology, Bonn, Germany
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Dorota Denkhaus
- University of Bonn, Department of Neuropathology, Bonn, Germany
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Anja zur Mühlen
- University of Bonn, Department of Neuropathology, Bonn, Germany
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Martin Mynarek
- University of Hamburg Medical Center, Pediatric Hematology / Oncology, Hamburg, Germany
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Stefan Rutkowski
- University of Hamburg Medical Center, Pediatric Hematology / Oncology, Hamburg, Germany
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Torsten Pietsch
- University of Bonn, Department of Neuropathology, Bonn, Germany
| Veröffentlicht: | 25. August 2015 |
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Gliederung
Text
The identification of desmoplastic/nodular histology as an independent favourable prognostic marker in medulloblastoma (MB) of infancy has allowed the reduction of therapy in these patients to decrease longterm side-effects. Although we were able to demonstrate different origins and pathway activation of desmoplastic versus non-desmoplastic MB, the genomics and pathway activation has not been exactly related to the different histological MB subtypes.
168 MBs of children under 5 years of age were diagnosed according to the WHO 2007 classification, and FFPE material was analysed in detail by immunohistochemical techniques (including staining of hedgehog targets YAP-1 and p75-NGFR) as well as by molecular inversion profiling (MIP) to assess the genomic landscape of infant MB. GISTIC analysis was performed to identify significant copy number alterations in MB subtypes.
MB with extensive nodularity (MBEN, n=22) and desmoplastic MB (DMB, n=42) were both characterized by LOH of chromosomal arms 9q or 10q (MBEN, 77% of cases; DMB, 76%), whereas classic MB (CMB, n=90) and large cell or anaplastic MBs (LCA-MB, n=14) frequently showed specific gains of chromosomal arm 17q (CMB, 67%; LCA-MB, 79%),partially occurring as isochromosome 17q (CMB, 30%; LCA-MB, 57%), and gains of OTX2 (CMB, 73%; LCA-MB, 79%). Moreover 10/14 (71%) of LCA-MB carried MYCC (n=9) or MYCN (n=1) amplifications. The overall frequency of chromosomal copy number aberrations was significantly lower in the desmoplastic/nodular subtypes compared to non-desmoplastic subtypes. Importantly, there was a high correlation between desmoplastic/nodular histology (MBEN and DMB) versus non-desmoplastic subtypes with hedgehog pathway activation shown by the expression of Yap-1 and p75-NGFR (concordance rate, >98%).
In summary, histology of infant MB is associated with specific recurrent chromosomal alterations and reflects their biology determined by their cellular origin and developmental pathway activation. Immunohistological assessment of pathway markers and genomic profiling by MIP can help to classify infant MBs.
