학술논문
Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors
Document Type
article
Author
Torchia, Jonathon; Golbourn, Brian; Feng, Shengrui; Ho, Ching; Sin-Chan, Patrick; Vasiljevic, Alexandre; Norman, Joseph D; Guilhamon, Paul; Garzia, Livia; Agamez, Natalia R; Lu, Mei; Chan, Tiffany S; Picard, Daniel; de Antonellis, Pasqualino; Khuong-Quang, Dong-Anh; Planello, Aline C; Zeller, Constanze; Barsyte-Lovejoy, Dalia; Lafay-Cousin, Lucie; Letourneau, Louis; Bourgey, Mathieu; Yu, Man; Gendoo, Deena MA; Dzamba, Misko; Barszczyk, Mark; Medina, Tiago; Riemenschneider, Alexandra N; Morrissy, A Sorana; Ra, Young-Shin; Ramaswamy, Vijay; Remke, Marc; Dunham, Christopher P; Yip, Stephen; Ng, Ho-keung; Lu, Jian-Qiang; Mehta, Vivek; Albrecht, Steffen; Pimentel, Jose; Chan, Jennifer A; Somers, Gino R; Faria, Claudia C; Roque, Lucia; Fouladi, Maryam; Hoffman, Lindsey M; Moore, Andrew S; Wang, Yin; Choi, Seung Ah; Hansford, Jordan R; Catchpoole, Daniel; Birks, Diane K; Foreman, Nicholas K; Strother, Doug; Klekner, Almos; Bognár, Laszló; Garami, Miklós; Hauser, Péter; Hortobágyi, Tibor; Wilson, Beverly; Hukin, Juliette; Carret, Anne-Sophie; Van Meter, Timothy E; Hwang, Eugene I; Gajjar, Amar; Chiou, Shih-Hwa; Nakamura, Hideo; Toledano, Helen; Fried, Iris; Fults, Daniel; Wataya, Takafumi; Fryer, Chris; Eisenstat, David D; Scheinemann, Katrin; Fleming, Adam J; Johnston, Donna L; Michaud, Jean; Zelcer, Shayna; Hammond, Robert; Afzal, Samina; Ramsay, David A; Sirachainan, Nongnuch; Hongeng, Suradej; Larbcharoensub, Noppadol; Grundy, Richard G; Lulla, Rishi R; Fangusaro, Jason R; Druker, Harriet; Bartels, Ute; Grant, Ronald; Malkin, David; McGlade, C Jane; Nicolaides, Theodore; Tihan, Tarik; Phillips, Joanna; Majewski, Jacek; Montpetit, Alexandre; Bourque, Guillaume; Bader, Gary D; Reddy, Alyssa T; Gillespie, G Yancey; Warmuth-Metz, Monika
Source
Cancer Cell. 30(6)
Subject
Language
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.