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Molecular subgrouping of atypical teratoid/rhabdoid tumors-a reinvestigation and current consensus
Ben Ho1, Pascal D Johann2,3,4, Yura Grabovska5
1Division of Hematology and Oncology, Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Ontario, Canada.
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We integrated various methods to perform a meta-analysis on published and unpublished DNA methylation and gene expression datasets of ATRTs and associated clinicopathological data.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.
Insights
Atypical teratoid/rhabdoid tumors (ATRTs) have three consensus molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. This classification aids research and refines therapies for ATRT patients.
Area of Science:
- Pediatric Oncology
- Molecular Pathology
- Genomics
Background:
- Atypical teratoid/rhabdoid tumors (ATRTs) display significant molecular and clinical heterogeneity.
- SMARCB1 inactivation is the primary genetic driver in nearly all ATRT cases.
- Previous studies identified distinct molecular subgroups, necessitating consensus on nomenclature and significance.
Purpose of the Study:
- To align previous findings on ATRT molecular subgroups.
- To establish a consensus nomenclature and define the clinicopathological significance of ATRT subgroups.
- To facilitate future research and therapeutic refinement for ATRT patients.
Main Methods:
- Meta-analysis of published and unpublished DNA methylation and gene expression datasets.
- Integration of ATRT molecular data with clinicopathological information.
- Utilized advanced bioinformatic and statistical analyses.
Main Results:
- Confirmed three main molecular subgroups of ATRTs: ATRT-TYR, ATRT-SHH, and ATRT-MYC.
- Identified further heterogeneity within the ATRT-SHH subgroup into ATRT-SHH-1 (supratentorial) and ATRT-SHH-2 (infratentorial) subtypes.
- Characterized molecular and clinical features, including SMARCB1 alterations and pathway activation, for each subgroup.
Conclusions:
- A consensus classification and nomenclature for ATRT subgroups have been established.
- This unified approach will standardize subgrouping of patient samples and models.
- Refined subgroup-based therapies are anticipated to improve outcomes for ATRT patients.
