Molecular subgrouping of atypical teratoid/rhabdoid tumors—a reinvestigation and current consensus

Abstract

Background Atypical teratoid/rhabdoid tumors (ATRTs) are known to exhibit molecular and clinical heterogeneity even though SMARCB1 inactivation is the sole recurrent genetic event present in nearly all cases. Indeed, recent studies demonstrated 3 molecular subgroups of ATRTs that are genetically, epigenetically, and clinically distinct. As these studies included different numbers of tumors, various subgrouping techniques, and naming, an international working group sought to align previous findings and to reach a consensus on nomenclature and clinicopathological significance of ATRT subgroups. Methods We integrated various methods to perform a meta-analysis on published and unpublished DNA methylation and gene expression datasets of ATRTs and associated clinicopathological data. Results In concordance with previous studies, the analyses identified 3 main molecular subgroups of ATRTs, for which a consensus was reached to name them ATRT-TYR, ATRT-SHH, and ATRT-MYC. The ATRT-SHH subgroup exhibited further heterogeneity, segregating further into 2 subtypes associated with a predominant supratentorial (ATRT-SHH-1) or infratentorial (ATRT-SHH-2) location. For each ATRT subgroup we provide an overview of its main molecular and clinical characteristics, including SMARCB1 alterations and pathway activation. Conclusions The introduction of a common classification, characterization, and nomenclature of ATRT subgroups will facilitate future research and serve as a common ground for subgrouping patient samples and ATRT models, which will aid in refining subgroup-based therapies for ATRT patients.

Analysis of Dual Class I Histone Deacetylase and Lysine Demethylase Inhibitor Domatinostat (4SC-202) on Growth and Cellular and Genomic Landscape of Atypical Teratoid/Rhabdoid

“…Significant differences in viability were observed between ATRT-06 as compared to NSC (p < 0.05), and between ATRT-06 and ATRT-05 compared to HEK-293 (p < 0.001), at 1 µM 4SC-202 treatment, according to paired two-tailed t-tests (Figure 2a,b). Recent studies examining the molecular subtyping of ATRT tumors indicate that ATRT-05 is most closely correlated with Group 1 ATRT (neurogenic, ATRT-SHH) and ATRT-06 with Group 2 ATRT (mesenchymal, ATRT-MYC) [31,32]. Additionally, in a spheroid model, treatment with 56 nM 4SC-202 significantly decreased spheroid growth when compared to a vehicle treatment with 0.02% DMSO ( Figure S2).…”

“…FOXM1 was also identified as the downstream target of MYC in prostate cancer [74]. This relationship between MYC and FOXM1 is of particular interest since MYC is one of the key distinguishing features of the ATRT-MYC type, and the cell line used for the single-cell RNA-sequencing experiment has recently been classified as ATRT-MYC type [31,32]. Inhibition of MYC has been demonstrated to decrease pluripotency-related pathways and tumor self-renewal [73,75], and is altered by HDACi's.…”

Advances in the molecular classification of pediatric brain tumors: a guide to the galaxy

“…Other studies have shown that loss of SMARCB4 is critical in ATRT development, but less frequent [115]. ATRTs encompass three epigenetic subgroups with distinct genomic profiles and SMARCB1 genotypes [116]. ATRT-TYR tumors are more common in the infratentorial regions, ATRT-MYC tumors are commonly seen in the supratentorial area, and ATRT-SHH tumors are seen in both infraand supra-tentorial areas.…”

“…Oncology Group ACNS0333 study, with some suggestion that ATRT-SHH benefit from high-dose chemotherapy approaches and ATRT-TYR benefit from radiotherapy [116,[118][119][120][121]. The EZH2 inhibitor tazemetostat is a rational approach to target the SWI/SNF complex and is being investigated in upcoming clinical trials; however, there is a paucity of early phase human data at the present time [122].…”

Genome-wide CRISPR and small-molecule screens uncover targetable dependencies in ATRT

“…In spite of their consistent homogeneity on the genetic level, ATRTs display a remarkable epigenetic and transcriptional heterogeneity (Johann et al, 2016;Torchia et al, 2016). Based on these studies, ATRTs are currently segregated into three molecular subgroups: ATRT-SHH (formerly group 1), ATRT-TYR (group 2A), and ATRT-MYC (group 2B) (Ho et al, 2020). Whereas these distinct molecular profiles clearly correlate with clinical features, such as patient age and tumor location, it remains elusive if these molecular subgroups also enable molecular-driven therapeutic strategies.…”