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 LetourneauMathieu 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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

89 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)891-908
Number of pages18
JournalCancer Cell
Volume30
Issue number6
DOIs
StatePublished - Dec 12 2016

Keywords

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

ASJC Scopus subject areas

  • Oncology
  • Cell Biology
  • Cancer Research

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