Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor
characterized by loss of SMARCB1/INI1 protein expression and comprises three distinct
molecular groups, ATRT-TYR, ATRT-MYC and ATRT-SHH. ATRT-SHH represents the largest
molecular group and is heterogeneous with regard to age, tumor location and epigenetic
profile. We, therefore, aimed to investigate if heterogeneity within ATRT-SHH might
also have biological and clinical importance. Consensus clustering of DNA methylation
profiles and confirmatory t-SNE analysis of 65 ATRT-SHH yielded three robust molecular
subgroups, i.e., SHH-1A, SHH-1B and SHH-2. These subgroups differed by median age
of onset (SHH-1A: 18 months, SHH-1B: 107 months, SHH-2: 13 months) and tumor location
(SHH-1A: 88% supratentorial; SHH-1B: 85% supratentorial; SHH-2: 93% infratentorial,
often extending to the pineal region). Subgroups showed comparable SMARCB1 mutational
profiles, but pathogenic/likely pathogenic SMARCB1 germline variants were over-represented
in SHH-2 (63%) as compared to SHH-1A (20%) and SHH-1B (0%). Protein expression of
proneural marker ASCL1 (enriched in SHH-1B) and glial markers OLIG2 and GFAP (absent
in SHH-2) as well as global mRNA expression patterns differed, but all subgroups were
characterized by overexpression of SHH as well as Notch pathway members. In a Drosophila
model, knockdown of Snr1 (the fly homologue of SMARCB1) in hedgehog activated cells
not only altered hedgehog signaling, but also caused aberrant Notch signaling and
formation of tumor-like structures. Finally, on survival analysis, molecular subgroup
and age of onset (but not ASCL1 staining status) were independently associated with
overall survival, older patients (> 3 years) harboring SHH-1B experiencing relatively
favorable outcome. In conclusion, ATRT-SHH comprises three subgroups characterized
by SHH and Notch pathway activation, but divergent molecular and clinical features.
Our data suggest that molecular subgrouping of ATRT-SHH has prognostic relevance and
might aid to stratify patients within future clinical trials.
