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

Abstract

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.

Inhibition of MYC attenuates tumor cell self‐renewal and promotes senescence in SMARCB1‐deficient Group 2 atypical teratoid rhabdoid tumors to suppress tumor growth in vivo

“…Our patient cohort segregates into 3 subgroups based on the Torchia gene classifier (Supporting Information, Fig. 1 a ) . Similarly, most commonly used ATRT cell lines from the Group2 subgroup also had high levels of MYC protein (Supporting Information, Figs.…”

“…identified a particularly poor‐outcome subgroup (Group 2) characterized by high BMP pathway activation comparable to our previous studies . More recently, two large studies have clustered ATRT into three subgroups based on transcriptomic and DNA‐methylation analysis . These studies suggest that differential enhancer activity and regulation of master transcriptional regulators are a key component of the ATRT transcriptomic landscape.…”

“…The data imply that transcriptional regulation of cell identity and lineage commitment is a key element of ATRT biology. Among the genomic subgroups, a subset of poor outcome high BMP expressing tumors (Group2), also express high levels of the MYC oncogene …”

Integrating RNA sequencing into neuro-oncology practice

“…(43) Nevertheless, DNA methylation profiling, whole-exome DNA sequencing, and RNA-seq have established three distinct molecular subgroups: ATRT-TYR, ATRT-MYC, ATRT-SHH, which have distinct gene expression profiles. (44, 45) ATRT-TYR is defined by an over-expression of the melanosomal markers DCT , MITF , or TYR and is frequently found infratentorially in children under 1 year of age. (44) ATRT-MYC tumors overexpress MYC and are most often supratentorial.…”

“…Many human cancers harboring the same histology and recurrent DNA alterations can be further characterized by widely distinct patterns of global gene expression. (2, 3) Transcriptional signatures now augment or surpass information on tumor biology and clinical prognosis provided by histology alone. (4) From a therapeutic perspective, changes in the sequence and quantity of RNA transcripts often translates into changes in their encoded proteins, resulting in cancer-specific druggable targets and immunogenic molecules.…”