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

• DOI: 10.1016/j.ccell.2016.11.003
• Publication Date: 2016-12-12T19:50:28Z
• 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 Ant...; Dong-Anh Khuong-Q...; Aline C. Planello; Constanze Zeller; Dalia Barsyte-Lov...; Lucie Lafay-Cousin; Louis Letourneau; Mathieu Bourgey; Man Yu; Deena M.A. Gendoo; Misko Dzamba; Mark Barszczyk; Tiago Medina; Alexandra N. Riem...; A. Sorana Morrissy; Young-Shin Ra; Vijay Ramaswamy; Marc Remke; Christopher P. Du...; 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 Larbchar...; 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-Eps...; Cheryl H. Arrowsmith; Daniel D. De Carv...; James T. Rutka; Nada Jabado; Annie Huang
• Keywords: Epigenomics; 0301 basic medicine; Dasatinib; ATRT; Epigenesis, Genetic; 1307 Cell Biology; Central Nervous System Neoplasms; Rhabdoid tumors; 2.1 Biological and endogenous factors; 1306 Cancer Research; Aetiology; Cancer; Tumor; Teratoma; Genomics; Orvostudományok; SMARCB1 Protein; Platelet-Derived Growth Factor beta; Chromatin; 3. Good health; 5.1 Pharmaceuticals; subgroup-specific therapeutics; 2730 Oncology; ATRT; enhancer; epigenomics; genomics; rhabdoid tumors; subgroup-specific therapeutics; Cell Line, Tumor; Cell Proliferation; Cell Survival; Central Nervous System Neoplasms; Chromatin; DNA Methylation; Dasatinib; Epigenesis, Genetic; Epigenomics; Humans; Mutation; Protein Kinase Inhibitors; Pyrimidines; Receptor, Platelet-Derived Growth Factor beta; Rhabdoid Tumor; SMARCB1 Protein; Teratoma; Development of treatments and therapeutic interventions; Receptor; Cell Survival; Oncology and Carcinogenesis; rhabdoid tumors; 610; Subgroup-specific therapeutics; Klinikai orvostudományok; Cell Line; Receptor, Platelet-Derived Growth Factor beta; 03 medical and health sciences; Rare Diseases; Genetic; Cell Line, Tumor; Genetics; genomics; Humans; Oncology & Carcinogenesis; Protein Kinase Inhibitors; Rhabdoid Tumor; Cell Proliferation; Human Genome; Neurosciences; DNA Methylation; Orphan Drug; Pyrimidines; epigenomics; Mutation; enhancer; Enhancer; Epigenesis

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.