ATRT–SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance

Abstract

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.

Survival Benefit from Multimodal Treatment for Patients with Atypical Teratoid Rhabdoid Tumor in a Surveillance, Epidemiology, and End Results Database Analysis

“…This is mostly due to the fact that ATRT has a complex histologic pattern of a combination of rhabdoid, epithelial, primitive neuroepithelial, and mesenchymal components. These histological patterns lead it to be commonly mistaken for medulloblastoma, choroid plexus carcinoma, or CNS primitive neuroectodermal tumor [5]. The ability to diagnose ATRT has only recently been made accessible due to the advent of immunohistochemical testing in the late 1990s [6].…”

Atypical teratoid/rhabdoid tumoroids reveal subgroup-specific drug vulnerabilities

“…While we observed consistent drug sensitivity across all screened ATRT-MYC models, ATRT-SHH tumoroid models displayed strong intertumoral differences in drug response. This could be explained by the recent observation that the ATRT-SHH subgroup can be further subdivided into three subgroups with different clinical outcomes [ 39 ]. Drug testing on larger collections of ATRT-SHH tumoroid models will be required to determine whether the observed differences in drug sensitivity are indeed caused by subgroup differences.…”

Rhabdoid tumor predisposition syndrome: A historical review of treatments and outcomes for associated pediatric malignancies

“…More recently, ATRT samples were evaluated from a cohort of 325 patients from the Hospital for Sick Children in Toronto and 65 patients from the Children's Oncology Group (COG) study ACNS0333, and results validated the molecular subgroupings and revealed that the 16% of patients with germline mutations had a 4‐year overall survival (OS) of only 20% 18,19 . There have been conflicting data between the COG study, European Rhabdoid Registry (EU‐RHAB), and St. Jude Children's Research Hospital with regard to whether the ATRT‐SHH 19 or ATRT‐TYR 20,21 subgroup has a better prognosis; recent work demonstrates that ATRT‐SHH may be further subdivided into three molecular subgroups associated with differing OS 22 . As a result, genomic subtyping may be helpful for prognosticating outcomes in RTPS and rhabdoid tumor variants 23,24 …”