Cribriform neuroepithelial tumor: molecular characterization of a SMARCB1‐deficient non‐rhabdoid tumor with favorable long‐term outcome |
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| Authors: | Pascal D. Johann Volker Hovestadt Christian Thomas Astrid Jeibmann Katharina Heß Susanne Bens Florian Oyen Cynthia Hawkins Christopher R. Pierson Kenneth Aldape Sang‐Pyo Kim Eva Widing David Sumerauer Péter Hauser Frank van Landeghem Marina Ryzhova Andrey Korshunov David Capper David T.W. Jones Stefan M. Pfister Reinhard Schneppenheim Reiner Siebert Werner Paulus Michael C. Frühwald Martin Hasselblatt |
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| Affiliation: | 1. Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany;2. German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany;3. Department of Pediatric Oncology and Hematology, University Hospital Heidelberg, Heidelberg, Germany;4. Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany;5. Institute of Neuropathology, University Hospital Münster, Münster, Germany;6. Institute of Human Genetics, University Ulm, Ulm, Germany;7. Department of Pediatric Hematology and Oncology, University Medical Center Hamburg‐Eppendorf, Hamburg, Germany;8. Division of Pathology, The Hospital for Sick Children, Toronto, Canada;9. Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital and Department of Pathology and Division of Anatomy, Ohio State University, Columbus, OH;10. Department of Laboratory Medicine and Pathology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada;11. Department of Pathology, Keimyung University Dongsan Medical Center, Daegu, Korea;12. Department of Pediatric Oncology, Oslo University Hospital, Oslo, Norway;13. Department of Pediatric Hematology and Oncology, University Hospital Motol, Charles University, 2nd Medical School, Prague, Czech Republic;14. 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary;15. Department of Laboratory Medicine & Pathology, Division of Anatomical Pathology, Neuropathology Specialty Group, University of Alberta, Edmonton, Canada;16. Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia;17. Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany;18. Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany;19. Swabian Childrens' Cancer Center, Childrens' Hospital Augsburg and EU‐RHAB Registry, Augsburg, Germany;20. Institute of Neuropathology, University Hospital Münster, Münster, GermanyMK and MH contributed equally |
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| Abstract: | Rhabdoid phenotype and loss of SMARCB1 expression in a brain tumor are characteristic features of atypical teratoid/rhabdoid tumors (ATRT). Rare non‐rhabdoid brain tumors showing cribriform growth pattern and SMARCB1 loss have been designated cribriform neuroepithelial tumor (CRINET). Small case series suggest that CRINETs may have a relatively favorable prognosis. However, the long‐term outcome is unclear and it remains uncertain whether CRINET represents a distinct entity or a variant of ATRT. Therefore, 10 CRINETs were clinically and molecularly characterized and compared with 10 ATRTs of each of three recently described molecular subgroups (i.e. ATRT‐TYR, ATRT‐SHH and ATRT‐MYC) using Illumina Infinium HumanMethylation450 arrays, FISH, MLPA, and sequencing. Furthermore, outcome was compared to a larger cohort of 27 children with ATRT‐TYR. Median age of the 6 boys and 4 girls harboring a CRINET was 20 months. On histopathological examination, all CRINETs demonstrated a cribriform growth pattern and distinct tyrosinase staining. On unsupervised cluster analysis of methylation data, all CRINETs examined exclusively clustered within the ATRT‐TYR molecular subgroup. As ATRT‐TYR, CRINETs mainly showed large heterozygous 22q deletions (9/10) and SMARCB1 mutations of the other allele. In two patients, SMARCB1 mutations were also present in the germline. Estimated mean overall survival in patients with CRINETs was 125 months (95% confidence interval 100–151 months) as compared to only 53 (33–74) months in patients with ATRTs of the ATRT‐TYR subgroup (Log‐Rank P < 0.05). In conclusion, CRINET represents a SMARCB1‐deficient non‐rhabdoid tumor, which shares molecular similarities with the ATRT‐TYR subgroup but has distinct histopathological features and favorable long‐term outcome. |
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| Keywords: | atypical teratoid/rhabdoid tumor copy number alterations DNA methylation profiling SMARCB1/INI1 tyrosinase |
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