ATRTs are comprised of three epigenetically distinct but genetically similar subgroups.

  • Major finding: ATRTs are comprised of three epigenetically distinct but genetically similar subgroups.

  • Concept: The clinical and molecular heterogeneity of ATRTs is explained by their epigenetic heterogeneity.

  • Impact: ATRT stratification may aid in the identification of subtype-specific targeted therapies.

Atypical teratoid/rhabdoid tumors (ATRT) are aggressive pediatric brain tumors characterized by biallelic loss of SMARCB1, which encodes an essential subunit of the SWI/SNF chromatin remodeling complex. Although ATRTs have an overall poor survival rate, some patients respond to therapy for reasons that remain unclear. Johann, Erkek, and colleagues characterized the genetic and epigenetic landscapes of 18 primary ATRTs to better understand this clinical heterogeneity. Whole-genome sequencing of primary ATRTs confirmed that these tumors have stable genomes, and SMARCB1 was the only highly recurrently altered gene. However, despite this shared genetic abnormality, DNA methylation and gene expression profiles of 192 ATRTs indicated that the tumors clustered into 3 clinically distinct molecular subgroups, which the authors termed ATRT-TYR, ATRT-SHH, and ATRT-MYC. The TYR tumors were characterized by overexpression of melanosomal marker genes, particularly tyrosinase (TYR), occurred primarily in the infratentorial regions of the brain, and were most common in very young children; the SHH subtype tumors exhibited high SHH and NOTCH signaling and occurred in both the supratentorial and infratentorial regions; and the MYC subtype tumors were distinguished by overexpression of MYC as well as HOX cluster genes, occurred most commonly in the supratentorial compartment, and were observed in older patients. Whole-genome bisulfite sequencing indicated that the ATRT-TYR and ATRT-SHH subgroup tumors had hypermethylated genomes, whereas ATRT-MYC tumors exhibited an increase in partially methylated domains. Chromatin immunoprecipitation sequencing identified subgroup-specific enhancers and superenhancers marked by histone 3 lysine 27 acetylation and BRD4 occupancy that were enriched for binding motifs for specific transcription factors, such as GLI2 in ATRT-SHH, MYC in ATRT-MYC, and OTX2 in ATRT-TYR, and indicated the presence of subtype-specific regulatory networks that could potentially be exploited for subtype-specific therapies. Altogether, these results indicate that ATRT is a genetically homogeneous but epigenetically heterogeneous disease, suggesting different potential cells of origin, which may help guide patient stratification and identify therapeutic targets.

Johann PD, Erkek S, Zapatka M, Kerl K, Buchhalter I, Hovestadt V, et al. Atypical teratoid/rhabdoid tumors are comprised of three epigenetic subgroups with distinct enhancer landscapes. Cancer Cell 2016;29:379–93.

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