title: Cribriform neuroepithelial tumor: molecular characterization of a SMARCB1-deficient non-rhabdoid tumor with favorable long-term outcome.
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.
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Department of Pediatric Oncology and Hematology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Pascal D
authors.initials: PD
authors.lastname: Johann
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Division of Molecular Genetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Volker
authors.initials: V
authors.lastname: Hovestadt
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thomas
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Astrid
authors.initials: A
authors.lastname: Jeibmann
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Heß
authors.affiliation: Institute of Human Genetics, University Ulm, Ulm, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Bens
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Florian
authors.initials: F
authors.lastname: Oyen
authors.affiliation: Division of Pathology, The Hospital for Sick Children, Toronto, Canada.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hawkins
authors.affiliation: Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital and Department of Pathology and Division of Anatomy, Ohio State University, Columbus, OH.
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Pierson
authors.affiliation: Department of Laboratory Medicine and Pathology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Aldape
authors.affiliation: Department of Pathology, Keimyung University Dongsan Medical Center, Daegu, Korea.
authors.forename: Sang-Pyo
authors.initials: SP
authors.lastname: Kim
authors.affiliation: Department of Pediatric Oncology, Oslo University Hospital, Oslo, Norway.
authors.forename: Eva
authors.initials: E
authors.lastname: Widing
authors.affiliation: Department of Pediatric Hematology and Oncology, University Hospital Motol, Charles University, 2nd Medical School, Prague, Czech Republic.
authors.forename: David
authors.initials: D
authors.lastname: Sumerauer
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Budapest, Hungary.
authors.forename: Péter
authors.initials: P
authors.lastname: Hauser
authors.affiliation: Department of Laboratory Medicine & Pathology, Division of Anatomical Pathology, Neuropathology Specialty Group, University of Alberta, Edmonton, Canada.
authors.forename: Frank
authors.initials: F
authors.lastname: van Landeghem
authors.affiliation: Department of Neuropathology, Burdenko Neurosurgical Institute, Moscow, Russia.
authors.forename: Marina
authors.initials: M
authors.lastname: Ryzhova
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Andrey
authors.initials: A
authors.lastname: Korshunov
authors.affiliation: German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Department of Neuropathology, University Hospital Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
authors.forename: David T W
authors.initials: DTW
authors.lastname: Jones
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.|Department of Pediatric Oncology and Hematology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Stefan M
authors.initials: SM
authors.lastname: Pfister
authors.affiliation: Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schneppenheim
authors.affiliation: Institute of Human Genetics, University Ulm, Ulm, Germany.
authors.forename: Reiner
authors.initials: R
authors.lastname: Siebert
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.affiliation: Swabian Childrens' Cancer Center, Childrens' Hospital Augsburg and EU-RHAB Registry, Augsburg, Germany.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Frühwald
authors.affiliation: Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|German Cancer Consortium (DKTK), Core Center Heidelberg, Heidelberg, Germany.
authors.forename: Marcel
authors.initials: M
authors.lastname: Kool
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
mesh_terms: D001932:Brain Neoplasms / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D009154:Mutation / Q000235:genetics*; D018302:Neoplasms, Neuroepithelial / Q000235:genetics* / Q000473:pathology; D018335:Rhabdoid Tumor / Q000235:genetics* / Q000473:pathology; D000071796:SMARCB1 Protein / Q000172:deficiency* / Q000235:genetics*; D018709:Statistics, Nonparametric
chemical_list: D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human
keywords: DNA methylation profiling; SMARCB1/INI1; atypical teratoid/rhabdoid tumor; copy number alterations; tyrosinase