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Lancet Oncol. 2015 May;16(5):569-82. doi: 10.1016/S1470-2045(15)70114-2. Epub 2015 Apr 14.

Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.

Author information

1
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.
2
Alberta Children's Hospital, and Departments of Oncology and Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
3
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.
4
Department of Neurosurgery, Seoul National University Children's Hospital, Seoul, South Korea.
5
Genome Quebec Innovation Centre, McGill University, Montreal, QC, Canada.
6
Department of Neurosurgery, Asan Medical Center, Songpa-gu, Seoul, South Korea.
7
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.
8
Division of Anatomic Pathology, Children's and Women's Health Centre of British Columbia, Vancouver, BC, Canada.
9
Department of Neuropathology, Vancouver General Hospital, Vancouver, BC, Canada.
10
Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China.
11
Department of Laboratory Medicine and Pathology, University of Alberta Hospital, Edmonton, AB, Canada.
12
Department of Pathology, Montreal Children's Hospital, McGill University Health Center Research Institute, Montreal, QC, Canada.
13
Department of Neurology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon, Portugal.
14
Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB, Canada.
15
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON, Canada.
16
Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal.
17
Cytogenetic Laboratory, Centro de Investigação em Patobiologia Molecular, Portuguese Cancer Institute, Lisbon, Portugal.
18
Department of Immunology, Genetics and Pathology, Uppsala University Hospital, Uppsala, Sweden.
19
Department of Pediatrics, University of Colorado Denver, Aurora, CO, USA.
20
Department of Neurosurgery, University of Debrecen, Debrecen, Hungary.
21
Second Department of Pediatrics, Semmelweis University, Budapest, Hungary.
22
Department of Histopathology, Faculty of Medicine, University of Szeged, Hungary.
23
Division of Pediatric Hematology/Oncology, Department of Pediatrics, University of Alberta, Edmonton, AB, Canada.
24
Division of Neurology and Oncology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
25
Division of Hematology-Oncology, Centre Hospitalier Universitaire Sainte-Justine, Université de Montréal, Montreal, QC, Canada.
26
Pediatric Hematology-Oncology, Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
27
Department of Neurosurgery, Kumamoto University, Kumamoto, Japan.
28
Oncology Department, Schneider Hospital, Petach Tikva, Israel.
29
Pediatric Hematology Oncology Department, Hadassah Hebrew University Hospital, Jerusalem, Israel.
30
Department of Neurosurgery, University of Utah, School of Medicine, Salt Lake City, UT, USA.
31
Department of Neurosurgery, Shizuoka Children's Hospital, Aoi-ku, Shizuoka, Japan.
32
Division of Hematology and Oncology, Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada.
33
Departments of Pediatrics and Medical Genetics, University of Alberta, Edmonton, AB, Canada.
34
Department of Pediatrics, McMaster University, Hamilton, ON, Canada.
35
Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada.
36
Department of Pathology and Laboratory Medicine, Ottawa Hospital and Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
37
Division of Children's Health and Therapeutics, Children's Health Research Institute, London, ON, Canada.
38
Department of Pathology, University of Western Ontario, London, ON, Canada.
39
Department of Pathology, London Health Sciences Centre, London, ON, Canada.
40
Division of Pediatric Hematology/Oncology, McMaster University, Hamilton, ON, Canada.
41
Division of Pediatrics-Hematology, Oncology and Stem Cell Transplantation, Ann and Robert H Lurie Children's Hospital of Chicago, Chicago, IL, USA.
42
Division of Hematology and Oncology, Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
43
Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.
44
Department of Pathology and Microbiology, Aga Khan University Hospital, Karachi, Pakistan.
45
Department of Clinical Research Services, Hospital for Sick Children, Toronto, ON, Canada.
46
Children's Brain Tumour Research Centre, School of Clinical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham, UK.
47
Center for Neuropathology, Ludwig-Maximilians-University, Munich, Germany.
48
Department of Pediatrics Hematology/Oncology, University of California, San Francisco, CA, USA.
49
Department of Pathology and Laboratory Medicine, University of California, San Francisco, CA, USA.
50
Department of Neurological Surgery, University of California, San Francisco, CA, USA.
51
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.
52
Department of Computer Science, Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, ON, Canada; Department of Molecular Genetics, University of Toronto, ON, Canada.
53
Department of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany.
54
Department of Paediatric Haematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
55
Department of Neuropathology, University of Bonn Medical Center, Bonn, Germany.
56
Department of Pathology and Laboratory Medicine at Children's Hospital Los Angeles, Los Angeles, CA, USA.
57
Department of Pediatrics, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada.
58
Division of Hematology-Oncology, University of Toronto, Toronto, ON, Canada; Department of Pediatrics, University of Toronto, Toronto, ON, Canada.
59
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.

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.

FINDINGS:

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.

INTERPRETATION:

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.

FUNDING:

C17 Research Network, Genome Canada, b.r.a.i.n.child, Mitchell Duckman, Tal Doron and Suri Boon foundations.

PMID:
25882982
DOI:
10.1016/S1470-2045(15)70114-2
[Indexed for MEDLINE]

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