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Published on: December 21, 2011
ATRT-SHH comprises three molecular subgroups with characteristic clinical and histopathological features and
Aniello Federico1,2, Christian Thomas3, Katarzyna Miskiewicz3
1Hopp Children's Cancer Center (KiTZ), Heidelberg, Germany.
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.
Insights
Atypical teratoid/rhabdoid tumor (ATRT)-SHH comprises three molecular subgroups with distinct clinical and biological features. Molecular subgrouping of ATRT-SHH offers prognostic relevance and aids in patient stratification for future clinical trials.
Area of Science:
- Neuro-oncology
- Molecular biology
- Genetics
Background:
- Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor with three molecular groups: ATRT-TYR, ATRT-MYC, and ATRT-SHH.
- ATRT-SHH is the largest subgroup but shows heterogeneity in age, location, and epigenetics, necessitating further investigation into its biological and clinical significance.
Purpose of the Study:
- To investigate the biological and clinical importance of heterogeneity within the ATRT-SHH molecular subgroup.
- To identify distinct molecular subgroups within ATRT-SHH and assess their prognostic relevance.
Main Methods:
- Consensus clustering and t-SNE analysis of DNA methylation profiles from 65 ATRT-SHH samples.
- Analysis of age of onset, tumor location, SMARCB1 mutational and germline profiles, and protein expression of key markers (ASCL1, OLIG2, GFAP).
- Utilized a Drosophila model to study the functional impact of SMARCB1 (Snr1) and pathway interactions.
Main Results:
- Identified three robust molecular subgroups within ATRT-SHH: SHH-1A, SHH-1B, and SHH-2, differing significantly in median age of onset and tumor location.
- Found over-representation of SMARCB1 germline variants in SHH-2, distinct protein expression patterns, and enrichment of proneural/glial markers in specific subgroups.
- Survival analysis revealed that molecular subgroup and age of onset were independent predictors of overall survival, with older patients in SHH-1B showing a favorable outcome.
Conclusions:
- ATRT-SHH is comprised of three distinct subgroups (SHH-1A, SHH-1B, SHH-2) characterized by SHH and Notch pathway activation but with divergent molecular and clinical features.
- Molecular subgrouping of ATRT-SHH demonstrates prognostic relevance.
- These findings may aid in stratifying ATRT-SHH patients for future clinical trials.
