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

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.

DOI: 10.1016/j.ccell.2016.11.003

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@article{Torchia2016IntegratedA, title={Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors.}, author={Jonathon Torchia and Brian Golbourn and Shengrui Feng and King Ching Ho and Patrick Sin-Chan and Alexandre Vasiljevic and Joseph D Norman and Paul Guilhamon and Livia Garzia and Natalia R Agamez and Mei Lu and Tiffany S Chan and Daniel Picard and Pasqualino de Antonellis and Dong-Anh Khuong-Quang and Aline C Planello and Constanze Zeller and Dalia Barsyte-Lovejoy and Lucie Lafay-Cousin and Louis Letourneau and Mathieu Bourgey and Man Yu and Deena M A Gendoo and Misko Dzamba and Mark Barszczyk and Tiago Medina and Alexandra N Riemenschneider and A Sorana Morrissy and Young-Shin Ra and Vijay Ramaswamy and Marc Remke and Christopher P Dunham and Stephen Yip and Ho-Keung Ng and Jian-Qiang Lu and Vivek Mehta and Steffen Albrecht and Jose Pimentel and Jennifer A Chan and Gino R Somers and Claudia C Faria and Lucia Roque and Maryam Fouladi and Lindsey M Hoffman and Andrew S Moore and Yin Wang and Seung Ah Choi and Jordan R Hansford and Daniel Catchpoole and Diane K Birks and Nicholas K Foreman and Doug Strother and Almos Klekner and Laszl{\'o} Bogn{\'a}r and Mikl{\'o}s Garami and P{\'e}ter Hauser and Tibor Hortob{\'a}gyi and Beverly Wilson and Juliette Hukin and Anne-Sophie Carret and Timothy E Van Meter and Eugene I Hwang and Amar Gajjar and Shih-Hwa Chiou and Hideo Nakamura and Helen Toledano and Iris Fried and Daniel Fults and Takafumi Wataya and Chris Fryer and David D Eisenstat and Katrin Scheinemann and Adam J Fleming and Donna L Johnston and Jean Michaud and Shayna Zelcer and Robert Hammond and Samina Afzal and David A Ramsay and Nongnuch Sirachainan and Suradej Hongeng and Noppadol Larbcharoensub and Richard G Grundy and Rishi R Lulla and Jason R Fangusaro and Harriet Druker and Ute Bartels and Ronald Grant and David Malkin and C Jane McGlade and Theodore Nicolaides and Tarik Tihan and Joanna Phillips and Jacek Majewski and Alexandre Montpetit and Guillaume Bourque and Gary D Bader and Alyssa T Reddy and G Yancey Gillespie and Monika Warmuth-Metz and Stefan Rutkowski and Uri Tabori and Mathieu Lupien and Michael Brudno and Ulrich Sch{\"{u}ller and Torsten Pietsch and Alexander R Judkins and Cynthia E Hawkins and Eric Bouffet and Seung-Ki Kim and Peter B Dirks and Michael D Taylor and Anat Erdreich-Epstein and Cheryl H Arrowsmith and Daniel D De Carvalho and James T Rutka and Nada Jabado and Annie Huang}, journal={Cancer cell}, year={2016}, volume={30 6}, pages={891-908} }