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

Torchia, Jonathon; Golbourn, Brian; Feng, Shengrui; Ching Ho, King; 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 M.A.; Dzamba, Misko; Barszczyk, Mark; Medina, Tiago; Riemenschneider, Alexandra N.; Morrissy, 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; Ah Choi, Seung; Hansford, Jordan R.; Catchpoole, Daniel; Birks, Diane K.; Foreman, Nicholas K.; Strother, Doug; Klekner, Almos; Bogn?r, Laszl?; Garami, Mikl?s; Hauser, P?ter; Hort...

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.

Citation

Torchia, J., Golbourn, B., Feng, S., Ching Ho, K., Sin-Chan, P., Vasiljevic, A., …Huang, A. (2016). Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors. Cancer Cell, 30(6), 891-908. https://doi.org/10.1016/j.ccell.2016.11.003

• Journal Article Type: Article
• Acceptance Date: Oct 31, 2016
• Online Publication Date: Dec 12, 2016
• Publication Date: Dec 12, 2016
• Deposit Date: Aug 25, 2017
• Journal: Cancer Cell
• Print ISSN: 1535-6108
• Electronic ISSN: 1878-3686
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 30
• Issue: 6
• Pages: 891-908
• DOI: https://doi.org/10.1016/j.ccell.2016.11.003
• Public URL: https://nottingham-repository.worktribe.com/output/1123871
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S1535610816305098
• PMID: 27960086