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

• Main Authors: 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
• Other Authors: University of Toronto
• Format: Article
• Published: 2018
• Subjects: Biochemistry, Genetics and Molecular Biology; Medicine
• Online Access: https://repository.li.mahidol.ac.th/handle/123456789/42259
• Institution: Mahidol University

© 2016 Elsevier Inc. 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.