Cancer Cell
Volume 30, Issue 6, 12 December 2016, Pages 891-908
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Article
Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors

https://doi.org/10.1016/j.ccell.2016.11.003Get rights and content
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Highlights

  • ATRTs comprise three molecular and epigenetic subgroups: group 1, 2A, and 2B

  • Distinct chromatin landscape drives subgroup-specific lineage and signaling features

  • ATRT subgroups exhibit distinct sensitivity to signaling and epigenetic inhibitors

  • Epigenetically regulated PDGFRB enhancer drives TKI sensitivity in group 2 ATRTs

Summary

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.

Keyword

ATRT
rhabdoid tumors
genomics
epigenomics
subgroup-specific therapeutics
enhancer

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