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

Jonathon Torchia; Brian Golbourn; Shengrui Feng; King Ching Ho; Patrick Sin-Chan; Alexandre Vasiljevic; Joseph D Norman; Paul Guilhamon; Livia Garzia; Natalia R Agamez; Mei Lu; Tiffany S Chan; Daniel Picard; Pasqualino de Antonellis; Dong-Anh Khuong-Quang; Aline C Planello; Constanze Zeller; Dalia Barsyte-Lovejoy; Lucie Lafay-Cousin; Louis Letourneau; Mathieu Bourgey; Man Yu; Deena M A Gendoo; Misko Dzamba; Mark Barszczyk; Tiago Medina; Alexandra N Riemenschneider; A Sorana Morrissy; Young-Shin Ra; Vijay Ramaswamy; Marc Remke; Christopher P Dunham; Stephen Yip; Ho-Keung Ng; Jian-Qiang Lu; Vivek Mehta; Steffen Albrecht; Jose Pimentel; Jennifer A Chan; Gino R Somers; Claudia C Faria; Lucia Roque; Maryam Fouladi; Lindsey M Hoffman; Andrew S Moore; Yin Wang; Seung Ah Choi; Jordan R Hansford; Daniel Catchpoole; Diane K Birks; Nicholas K Foreman; Doug Strother; Almos Klekner; Laszló Bognár; Miklós Garami; Péter Hauser; Tibor Hortobágyi; Beverly Wilson; Juliette Hukin; Anne-Sophie Carret; Timothy E Van Meter; Eugene I Hwang; Amar Gajjar; Shih-Hwa Chiou; Hideo Nakamura; Helen Toledano; Iris Fried; Daniel Fults; Takafumi Wataya; Chris Fryer; David D Eisenstat; Katrin Scheinemann; Adam J Fleming; Donna L Johnston; Jean Michaud; Shayna Zelcer; Robert Hammond; Samina Afzal; David A Ramsay; Nongnuch Sirachainan; Suradej Hongeng; Noppadol Larbcharoensub; Richard G Grundy; Rishi R Lulla; Jason R Fangusaro; Harriet Druker; Ute Bartels; Ronald Grant; David Malkin; C Jane McGlade; Theodore Nicolaides; Tarik Tihan; Joanna Phillips; Jacek Majewski; Alexandre Montpetit; Guillaume Bourque; Gary D Bader; Alyssa T Reddy; G Yancey Gillespie; Monika Warmuth-Metz; Stefan Rutkowski; Uri Tabori; Mathieu Lupien; Michael Brudno; Ulrich Schüller; Torsten Pietsch; Alexander R Judkins; Cynthia E Hawkins; Eric Bouffet; Seung-Ki Kim; Peter B Dirks; Michael D Taylor; Anat Erdreich-Epstein; Cheryl H Arrowsmith; Daniel D De Carvalho; James T Rutka; Nada Jabado; Annie Huang

doi:10.1016/j.ccell.2016.11.003

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

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

Authors

Jonathon Torchia¹, Brian Golbourn², Shengrui Feng³, King Ching Ho⁴, Patrick Sin-Chan¹, Alexandre Vasiljevic⁵, Joseph D Norman⁴, Paul Guilhamon⁶, Livia Garzia⁷, Natalia R Agamez⁴, Mei Lu⁴, Tiffany S Chan¹, Daniel Picard⁴, Pasqualino de Antonellis⁷, Dong-Anh Khuong-Quang⁸, Aline C Planello⁶, Constanze Zeller⁶, Dalia Barsyte-Lovejoy⁶, Lucie Lafay-Cousin⁹, Louis Letourneau¹⁰, Mathieu Bourgey¹⁰, Man Yu¹¹, Deena M A Gendoo⁴, Misko Dzamba¹², Mark Barszczyk¹¹, Tiago Medina⁶, Alexandra N Riemenschneider¹³, A Sorana Morrissy⁷, Young-Shin Ra¹⁴, Vijay Ramaswamy⁴, Marc Remke⁴, Christopher P Dunham¹⁵, Stephen Yip¹⁶, Ho-Keung Ng¹⁷, Jian-Qiang Lu¹⁸, Vivek Mehta¹⁹, Steffen Albrecht²⁰, Jose Pimentel²¹, Jennifer A Chan²², Gino R Somers²³, Claudia C Faria²⁴, Lucia Roque²⁵, Maryam Fouladi²⁶, Lindsey M Hoffman²⁷, Andrew S Moore²⁸, Yin Wang²⁹, Seung Ah Choi³⁰, Jordan R Hansford³¹, Daniel Catchpoole³², Diane K Birks²⁷, Nicholas K Foreman²⁷, Doug Strother³³, Almos Klekner³⁴, Laszló Bognár³⁴, Miklós Garami³⁵, Péter Hauser³⁵, Tibor Hortobágyi³⁶, Beverly Wilson³³, Juliette Hukin³⁷, Anne-Sophie Carret³⁸, Timothy E Van Meter³⁹, Eugene I Hwang⁴⁰, Amar Gajjar⁴¹, Shih-Hwa Chiou⁴², Hideo Nakamura⁴³, Helen Toledano⁴⁴, Iris Fried⁴⁵, Daniel Fults⁴⁶, Takafumi Wataya⁴⁷, Chris Fryer³⁷, David D Eisenstat³³, Katrin Scheinemann⁴⁸, Adam J Fleming⁴⁸, Donna L Johnston⁴⁹, Jean Michaud⁵⁰, Shayna Zelcer⁵¹, Robert Hammond⁵², Samina Afzal⁵³, David A Ramsay⁵², Nongnuch Sirachainan⁵⁴, Suradej Hongeng⁵⁴, Noppadol Larbcharoensub⁵⁵, Richard G Grundy⁵⁶, Rishi R Lulla⁵⁷, Jason R Fangusaro⁵⁷, Harriet Druker⁵⁸, Ute Bartels⁵⁸, Ronald Grant⁵⁸, David Malkin⁵⁹, C Jane McGlade⁶⁰, Theodore Nicolaides⁶¹, Tarik Tihan⁶², Joanna Phillips⁶², Jacek Majewski⁶³, Alexandre Montpetit¹⁰, Guillaume Bourque⁶³, Gary D Bader⁶⁴, Alyssa T Reddy⁶⁵, G Yancey Gillespie⁶⁶, Monika Warmuth-Metz⁶⁷, Stefan Rutkowski⁶⁸, Uri Tabori⁶⁹, Mathieu Lupien³, Michael Brudno⁷⁰, Ulrich Schüller⁷¹, Torsten Pietsch⁷², Alexander R Judkins⁷³, Cynthia E Hawkins⁷⁴, Eric Bouffet⁴, Seung-Ki Kim³⁰, Peter B Dirks¹³, Michael D Taylor⁷⁵, Anat Erdreich-Epstein⁷⁶, Cheryl H Arrowsmith⁶, Daniel D De Carvalho⁷⁷, James T Rutka⁷⁸, Nada Jabado⁷⁹, Annie Huang⁸⁰

Affiliations

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: [email protected].
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: [email protected].
⁷⁹ Department of Pediatrics, McGill University, Montreal, QC H3Z2Z3, Canada; Department of Human Genetics, McGill University, Montreal, QC H3Z2Z3, Canada. Electronic address: [email protected].
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: [email protected].

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.

MeSH terms

Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Central Nervous System Neoplasms / drug therapy
Central Nervous System Neoplasms / genetics*
Chromatin / genetics*
DNA Methylation
Dasatinib / pharmacology
Dasatinib / therapeutic use
Epigenesis, Genetic / drug effects
Epigenomics / methods*
Humans
Mutation
Protein Kinase Inhibitors / pharmacology
Protein Kinase Inhibitors / therapeutic use
Pyrimidines / pharmacology
Pyrimidines / therapeutic use
Receptor, Platelet-Derived Growth Factor beta / antagonists & inhibitors
Receptor, Platelet-Derived Growth Factor beta / genetics*
Rhabdoid Tumor / drug therapy
Rhabdoid Tumor / genetics*
SMARCB1 Protein / genetics*
Teratoma / drug therapy
Teratoma / genetics*

Substances

Chromatin
Protein Kinase Inhibitors
Pyrimidines
SMARCB1 Protein
SMARCB1 protein, human
PDGFRB protein, human
Receptor, Platelet-Derived Growth Factor beta
nilotinib
Dasatinib

Supplementary concepts

Typical Teratoid Rhabdoid Tumor

Abstract

MeSH terms

Substances

Supplementary concepts

Grants and funding