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Integrated (epi)-Genomic Analyses Identify Subgroup-Specific Therapeutic Targets in CNS Rhabdoid Tumors
Jonathon Torchia1, Brian Golbourn2, Shengrui Feng3
1Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5G0A4, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G0A4, Canada; Division of Hematology/Oncology, Hospital for Sick Children, Toronto, ON M5G1X8, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, Hospital for Sick Children, Toronto, ON M5G1X8, Canada.
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.
Insights
Atypical teratoid rhabdoid tumors (ATRTs) have three epigenetic subgroups with distinct genomic profiles. Group 2 ATRT cells show sensitivity to dasatinib and nilotinib, offering potential new therapies for this lethal brain tumor.
Area of Science:
- Pediatric Oncology
- Cancer Genomics
- Epigenetics
Background:
- Atypical teratoid rhabdoid tumors (ATRTs) are aggressive pediatric brain tumors.
- Previous research identified transcriptional subtypes with varied clinical outcomes.
- Mechanisms driving therapeutic heterogeneity in ATRTs remain largely unknown.
Purpose of the Study:
- To define the genomic and epigenomic landscape of ATRTs.
- To identify subgroup-specific therapeutic targets.
- To understand the basis of differential treatment responses in ATRT subtypes.
Main Methods:
- Analysis of 191 primary ATRTs and 10 ATRT cell lines.
- Genomic and epigenomic profiling.
- Assessment of cellular responses to signaling and epigenetic inhibitors.
Main Results:
- ATRTs were classified into three distinct epigenetic subgroups.
- These subgroups exhibited unique genomic profiles, SMARCB1 genotypes, and chromatin landscapes.
- Differential methylation of a PDGFRB enhancer identified group 2 ATRT sensitivity to dasatinib and nilotinib.
Conclusions:
- Epigenetic subgrouping provides a framework for understanding ATRT heterogeneity.
- Targeted therapies like dasatinib and nilotinib show promise for specific ATRT subtypes.
- Further investigation into PDGFRB-driven pathways may yield novel therapeutic strategies.
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