Format

Send to

Choose Destination
Cancer Cell. 2016 Dec 12;30(6):891-908. doi: 10.1016/j.ccell.2016.11.003.

Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.

Torchia J1, Golbourn B2, Feng S3, Ho KC4, Sin-Chan P1, Vasiljevic A5, Norman JD4, Guilhamon P6, Garzia L7, Agamez NR4, Lu M4, Chan TS1, Picard D4, de Antonellis P7, Khuong-Quang DA8, Planello AC6, Zeller C6, Barsyte-Lovejoy D6, Lafay-Cousin L9, Letourneau L10, Bourgey M10, Yu M11, Gendoo DMA4, Dzamba M12, Barszczyk M11, Medina T6, Riemenschneider AN13, Morrissy AS7, Ra YS14, Ramaswamy V4, Remke M4, Dunham CP15, Yip S16, Ng HK17, Lu JQ18, Mehta V19, Albrecht S20, Pimentel J21, Chan JA22, Somers GR23, Faria CC24, Roque L25, Fouladi M26, Hoffman LM27, Moore AS28, Wang Y29, Choi SA30, Hansford JR31, Catchpoole D32, Birks DK27, Foreman NK27, Strother D33, Klekner A34, Bognár L34, Garami M35, Hauser P35, Hortobágyi T36, Wilson B33, Hukin J37, Carret AS38, Van Meter TE39, Hwang EI40, Gajjar A41, Chiou SH42, Nakamura H43, Toledano H44, Fried I45, Fults D46, Wataya T47, Fryer C37, Eisenstat DD33, Scheinemann K48, Fleming AJ48, Johnston DL49, Michaud J50, Zelcer S51, Hammond R52, Afzal S53, Ramsay DA52, Sirachainan N54, Hongeng S54, Larbcharoensub N55, Grundy RG56, Lulla RR57, Fangusaro JR57, Druker H58, Bartels U58, Grant R58, Malkin D59, McGlade CJ60, Nicolaides T61, Tihan T62, Phillips J62, Majewski J63, Montpetit A10, Bourque G63, Bader GD64, Reddy AT65, Gillespie GY66, Warmuth-Metz M67, Rutkowski S68, Tabori U69, Lupien M3, Brudno M70, Schüller U71, Pietsch T72, Judkins AR73, Hawkins CE74, Bouffet E4, Kim SK30, Dirks PB13, Taylor MD75, Erdreich-Epstein A76, Arrowsmith CH6, De Carvalho DD77, Rutka JT78, Jabado N79, Huang A80.

Author information

1
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G0A4, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G0A4, Canada; Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
2
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G0A4, Canada; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
3
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G0A4, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G1L7, Canada.
4
Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
5
Department of Pathology, Groupement Hospitalier Est, CHU de Lyon, Lyon-Bron 69677, France.
6
Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G1L7, Canada.
7
Program in Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
8
Department of Pediatrics, McGill University, Montreal, QC H3Z2Z3, Canada; Department of Human Genetics, McGill University, Montreal, QC H3Z2Z3, Canada.
9
Division of Pediatric Hematology/Oncology, Alberta Children's Hospital, AB T3B6A8, Canada.
10
Genome Quebec Innovation Centre, McGill University, Montreal, QC H3A1A4, Canada.
11
Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
12
Department of Computer Science, University of Toronto, Toronto, ON M5G0A4, Canada.
13
Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
14
Department of Neurosurgery, Asan Medical Center, Seoul 138-736, Korea.
15
Division of Anatomic Pathology, Children's and Women's Health Centre of B.C, University of British Columbia, Vancouver, BC V6H3N1, Canada.
16
Department of Pathology & Laboratory Medicine, University of British Columbia, V6T1Z3, Canada.
17
Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China.
18
Laboratory Medicine and Pathology, Stollery Children's Hospital, University of Alberta, Edmonton, AB T2W3N2, Canada.
19
Division of Neurosurgery, Stollery Children's Hospital, University of Alberta, Edmonton, AB T2W3N2, Canada.
20
Department of Pathology, McGill University, Montreal, QC H3Z2Z3, Canada.
21
Divison of Pathology, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon 1649-035, Portugal.
22
Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB T2N1N4, Canada.
23
Department of Paediatric Laboratory Medicine, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
24
Department of Neurosurgery, Hospital de Santa Maria, Centro Hospitalar Lisboa Norte, Lisbon 1649-035, Portugal.
25
Cytometry and Cytogenetic Laboratory, CIPM, Portuguese Cancer Institute, Lisbon 1099-023, Portugal.
26
Division of Oncology, Department of Cancer and Blood Diseases, Cincinnati Children's Hospital, Cincinnati, OH 45229, USA.
27
Department of Pediatrics, University of Colorado, Denver, CO 80045, USA.
28
Oncology Service, Children's Health Queensland Hospital; University of Queensland Diamantina Institute, Brisbane, QLD 4102, Australia.
29
Research Institute of Health Development Strategies, Fudan University, Shanghai 200032, China.
30
Division of Pediatric Neurosurgery, Seoul National University Children's Hospital, Seoul 03080, Korea.
31
Royal Children's Hospital, Murdoch Children's Research Institute, Melbourne, VIC 3052, Australia.
32
Children's Cancer Research Unit, Children's Hospital at Westmead, Westmead, NSW 2145, Australia.
33
Division of Pediatric Hematology/Oncology, Stollery Children's Hospital, University of Alberta, Edmonton, AB T2W3N2, Canada.
34
Department of Neurosurgery, University of Debrecen, Debrecen 4032, Hungary.
35
Second Department of Pediatrics, Semmelweis University, Budapest 1094, Hungary.
36
Department of Histopathology, University of Szeged, Szeged 6720, Hungary.
37
Division of Hematology and Oncology, Children's and Women's Health Centre of B.C, University of British Columbia, Vancouver, BC V6H3N1, Canada.
38
Department of Pediatrics, Division of Hematology-Oncology, Université de Montréal/CHU Sainte-Justine, Montreal, QC H3T1C5, Canada.
39
Department of Neurosurgery, Virginia Commonwealth University, Richmond, VA 23298-0631, USA.
40
Department of Oncology, Children's National Medical Center, Washington, DC 20010, USA.
41
Division of Neuro-Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
42
Department of Medical Research, Taipei Veterans General Hospital and National Yang-Ming University, Taipei 112, Taiwan.
43
Department of Neurosurgery, Kumamoto University, Kumamoto 860-8556, Japan.
44
Department of Pediatric Hematology Oncology, Children's Medical Center of Israel, Petach Tikva 49202, Isreal.
45
Department of Pediatric Hematology-Oncology, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.
46
Department of Neurosurgery, University of Utah, School of Medicine, Salt Lake City, UT 84132, USA.
47
Department of Neurosurgery, Shizuoka Children's Hospital, Shizuoka 420-8660, Japan.
48
Department of Pediatrics, McMaster University, Hamilton, ON L8S4K1, Canada.
49
Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1H8L1, Canada.
50
Pathology and Laboratory Medicine, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, ON K1H8L1, Canada.
51
Division of Pediatric Hematology/Oncology, Children's Hospital, London Health Sciences Center, London, ON N6A5A5, Canada.
52
Department of Pathology and Laboratory Medicine, Children's Hospital of Western Ontario, University of Western Ontario, London, ON N6A5W9, Canada.
53
Department of Pediatrics, Dalhousie University, Halifax, NS B3H4R2, Canada.
54
Department of Pediatrics, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10300, Thailand.
55
Department of Pathology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand.
56
Children's Brain Tumour Research Centre, University of Nottingham, Nottingham NG72RD, England.
57
Division of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, IL 60611, USA.
58
Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
59
Department of Paediatrics, University of Toronto, Toronto, ON M5G0A4, Canada; Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Program in Genetics & Genome Biology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
60
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G0A4, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
61
Department of Pediatrics (Hematology/Oncology), University of California, San Francisco, San Francisco, CA 94143-0112, USA.
62
Department of Neurosurgery, University of California, San Francisco, San Francisco, CA 94143-0112, USA.
63
Department of Human Genetics, McGill University, Montreal, QC H3Z2Z3, Canada; Genome Quebec Innovation Centre, McGill University, Montreal, QC H3A1A4, Canada.
64
Department of Molecular Genetics, University of Toronto, Toronto, ON M5G0A4, Canada.
65
Department of Pediatric Hematology and Oncology, University of Alabama, Birmingham, AL 35233, USA.
66
Department of Neurosurgery, University of Alabama, Birmingham, AL 35233, USA.
67
Department of Neuroradiology, University of Würzburg, Würzburg 97070, Germany.
68
Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
69
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G0A4, Canada; Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Program in Genetics & Genome Biology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
70
Department of Computer Science, University of Toronto, Toronto, ON M5G0A4, Canada; Program in Genetics & Genome Biology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
71
Department of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
72
Institute for Neuropathology, University of Bonn Medical Center, Bonn 53105, Germany.
73
Department of Pathology & Laboratory Medicine, Children's Hospital of Los Angeles, Los Angeles, CA 90027, USA.
74
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G0A4, Canada; Division of Pathology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
75
Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Program in Developmental & Stem Cell Biology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
76
Department of Pediatrics, Children's Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA.
77
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G0A4, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, ON M5G1L7, Canada. Electronic address: ddecarv@uhnresearch.ca.
78
Department of Surgery, University of Toronto, Toronto, ON M5G0A4, Canada; Division of Neurosurgery, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada. Electronic address: james.rutka@sickkids.ca.
79
Department of Pediatrics, McGill University, Montreal, QC H3Z2Z3, Canada; Department of Human Genetics, McGill University, Montreal, QC H3Z2Z3, Canada. Electronic address: nada.jabado@mcgill.ca.
80
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G0A4, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G0A4, Canada; Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada. Electronic address: annie.huang@sickkids.ca.

Abstract

We recently reported that atypical teratoid rhabdoid tumors (ATRTs) comprise at least two transcriptional subtypes with different clinical outcomes; however, the mechanisms underlying therapeutic heterogeneity remained unclear. In this study, we analyzed 191 primary ATRTs and 10 ATRT cell lines to define the genomic and epigenomic landscape of ATRTs and identify subgroup-specific therapeutic targets. We found ATRTs segregated into three epigenetic subgroups with distinct genomic profiles, SMARCB1 genotypes, and chromatin landscape that correlated with differential cellular responses to a panel of signaling and epigenetic inhibitors. Significantly, we discovered that differential methylation of a PDGFRB-associated enhancer confers specific sensitivity of group 2 ATRT cells to dasatinib and nilotinib, and suggest that these are promising therapies for this highly lethal ATRT subtype.

KEYWORDS:

ATRT; enhancer; epigenomics; genomics; rhabdoid tumors; subgroup-specific therapeutics

PMID:
27960086
PMCID:
PMC5500911
DOI:
10.1016/j.ccell.2016.11.003
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center