title: Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.
abstract: BACKGROUND
  Rhabdoid brain tumours, also called atypical teratoid rhabdoid tumours, are lethal childhood cancers with characteristic genetic alterations of SMARCB1/hSNF5. Lack of biological understanding of the substantial clinical heterogeneity of these tumours restricts therapeutic advances. We integrated genomic and clinicopathological analyses of a cohort of patients with atypical teratoid rhabdoid tumours to find out the molecular basis for clinical heterogeneity in these tumours.
  
  
  METHODS
  We obtained 259 rhabdoid tumours from 37 international institutions and assessed transcriptional profiles in 43 primary tumours and copy number profiles in 38 primary tumours to discover molecular subgroups of atypical teratoid rhabdoid tumours. We used gene and pathway enrichment analyses to discover group-specific molecular markers and did immunohistochemical analyses on 125 primary tumours to evaluate clinicopathological significance of molecular subgroup and ASCL1-NOTCH signalling.
  
  
  RESULTS
  Transcriptional analyses identified two atypical teratoid rhabdoid tumour subgroups with differential enrichment of genetic pathways, and distinct clinicopathological and survival features. Expression of ASCL1, a regulator of NOTCH signalling, correlated with supratentorial location (p=0·004) and superior 5-year overall survival (35%, 95% CI 13-57, and 20%, 6-34, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·033) in 70 patients who received multimodal treatment. ASCL1 expression also correlated with superior 5-year overall survival (34%, 7-61, and 9%, 0-21, for ASCL1-positive and ASCL1-negative tumours, respectively; p=0·001) in 39 patients who received only chemotherapy without radiation. Cox hazard ratios for overall survival in patients with differential ASCL1 enrichment treated with chemotherapy with or without radiation were 2·02 (95% CI 1·04-3·85; p=0·038) and 3·98 (1·71-9·26; p=0·001). Integrated analyses of molecular subgroupings with clinical prognostic factors showed three distinct clinical risk groups of tumours with different therapeutic outcomes.
  
  
  CONCLUSIONS
  An integration of clinical risk factors and tumour molecular groups can be used to identify patients who are likely to have improved long-term radiation-free survival and might help therapeutic stratification of patients with atypical teratoid rhabdoid tumours.
  
  
  BACKGROUND
  C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.
authors.affiliation: Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Torchia
authors.affiliation: Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
authors.forename: Daniel
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authors.lastname: Picard
authors.affiliation: Alberta Children's Hospital, and Departments of Oncology and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Lucie
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authors.lastname: Lafay-Cousin
authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pathology, Hospital for Sick Children, Toronto, ON, Canada.
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authors.initials: CE
authors.lastname: Hawkins
authors.affiliation: Department of Neurosurgery, Seoul National University Children's Hospital, Seoul, South Korea.
authors.forename: Seung-Ki
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authors.lastname: Kim
authors.affiliation: Genome Quebec Innovation Centre, McGill University, Montreal, QC, Canada.
authors.forename: Louis
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authors.lastname: Letourneau
authors.affiliation: Department of Neurosurgery, Asan Medical Center, Songpa-gu, Seoul, South Korea.
authors.forename: Young-Shin
authors.initials: YS
authors.lastname: Ra
authors.affiliation: Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada.
authors.forename: King Ching
authors.initials: KC
authors.lastname: Ho
authors.affiliation: Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
authors.forename: Tiffany Sin Yu
authors.initials: TS
authors.lastname: Chan
authors.affiliation: Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
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authors.affiliation: Division of Anatomic Pathology, Children's and Women's Health Centre of British Columbia, Vancouver, BC, Canada.
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authors.initials: CP
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authors.affiliation: Department of Neuropathology, Vancouver General Hospital, Vancouver, BC, Canada.
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authors.affiliation: Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China.
authors.forename: Ho-Keung
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authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Edmonton, AB, Canada.
authors.forename: Jian-Qiang
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authors.affiliation: Department of Pathology, Montreal Children's Hospital, McGill University Health Center Research Institute, Montreal, QC, Canada.
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authors.affiliation: Department of Neurology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.
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authors.affiliation: Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
authors.forename: Jennifer A
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authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada.
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authors.initials: GR
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authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada.
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authors.affiliation: Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
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authors.affiliation: Alberta Children's Hospital, and Departments of Oncology and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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authors.affiliation: Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
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authors.affiliation: Division of Children's Health and Therapeutics, Children's Health Research Institute, London, ON, Canada.
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authors.affiliation: Department of Pathology, University of Western Ontario, London, ON, Canada.
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authors.affiliation: Division of Pediatrics-Hematology, Oncology and Stem Cell Transplantation, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
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authors.affiliation: Genome Quebec Innovation Centre, McGill University, Montreal, QC, Canada.
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authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, CA, USA.
authors.forename: Joanna
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authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada.
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authors.initials: MD
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authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada.
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authors.initials: JT
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authors.affiliation: Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON, Canada.
authors.forename: Peter
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authors.initials: GD
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authors.affiliation: Department of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Monika
authors.initials: M
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authors.affiliation: Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
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authors.affiliation: Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
authors.forename: Torsten
authors.initials: T
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authors.affiliation: Department of Pathology and Laboratory Medicine at Children's Hospital Los Angeles, Los Angeles, CA, USA.
authors.forename: Alexander R
authors.initials: AR
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authors.affiliation: Department of Pediatrics, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.
authors.forename: Nada
authors.initials: N
authors.lastname: Jabado
authors.affiliation: Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Bouffet
authors.affiliation: Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, University of Toronto, Toronto, ON, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada. Electronic address: annie.huang@sickkids.ca.
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authors.lastname: Huang
mesh_terms: D051792:Basic Helix-Loop-Helix Proteins / Q000096:biosynthesis* / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D023281:Genomics; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D011379:Prognosis; D051880:Receptors, Notch / Q000096:biosynthesis* / Q000235:genetics; D018335:Rhabdoid Tumor / Q000235:genetics* / Q000473:pathology; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics; D013724:Teratoma / Q000235:genetics* / Q000473:pathology
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D051880:Receptors, Notch; C065500:ASCL1 protein, human