Abstract Background Atypical teratoid/rhabdoid tumor (ATRT) is a rare and highly aggressive pediatric central nervous system malignancy, molecularly defined by inactivation of the SMARCB1 gene and dysfunction of the SWI/SNF chromatin-remodeling complex. Despite its biological aggressiveness, ATRT is characterized by a relatively simple genomic landscape, and comprehensive molecular profiling remains essential to identify potential therapeutic targets. Methods We analyzed the somatic genomic profile of 14 patients diagnosed with ATRT and treated at Bambino Gesù Children’s Hospital (Rome) between 2015 and 2025. Formalin-fixed paraffin-embedded (FFPE) tumor samples were analyzed using next-generation sequencing (NGS) with the Illumina TruSight™ Oncology 500 panel and, in selected cases, MSK-IMPACT®/MSK-IMPACT-FLEX®. Analyses included single nucleotide variants, small insertions/deletions, copy number alterations (CNA), microsatellite instability (MSI), and tumor mutational burden (TMB). Results Somatic alterations of SMARCB1 were identified in 93% of patients. Eleven patients harbored known pathogenic SMARCB1 alterations, including truncating mutations (nonsense or frameshift) and/or biallelic gene loss, frequently associated with monosomy or large deletions of chromosome 22. Several cases showed loss of heterozygosity involving the chr22q11.21–22q13.2 region, encompassing SMARCB1 and additional relevant genes (RAC2, CRKL, CHEK2, ZNRF3, LZTR1, MAPK1, NF2, and EP300), consistent with functional inactivation of the SWI/SNF complex. Two patients carried SMARCB1 variants of uncertain significance (VUS). Accessory genomic alterations were identified in 9 patients including losses of NF2, CHEK2, BCR, and CDKN2A/B, as well as alterations involving genes in the MAPK signaling pathway. Other accessory variants, predominantly classified as VUS, were identified in POLD1, MYC, UPF1, CIC, PMS2, SDHA, and USH2A. A potentially actionable missense mutation in ALK was detected in one patient. TMB was consistently low in all evaluable cases, and all tumors were microsatellite stable. Conclusions ATRTs in our cohort display a genomic profile dominated by pathogenic SMARCB1 loss and low mutational complexity, confirming the predominantly epigenetic-driven nature of this disease. While recurrent actionable alterations are rare, selected cases may harbor targetable genomic events, supporting the role of comprehensive molecular profiling to inform precision therapeutic strategies.
Forestiero et al. (Tue,) studied this question.