超罕见儿童恶性横纹肌样瘤基因组图谱的综合分析

Malignant rhabdoid tumors (MRTs) are ultra-rare, highly aggressive pediatric tumors that occur predominantly in infants, with the highest incidence in children under one year of age. MRTs exhibit high metastatic potential and poor prognosis, with 5-year event-free survival rates below 20%. There are currently no effective therapies for these patients. To better elucidate the molecular mechanisms driving MRT and identify potential therapeutic vulnerabilities, we constructed a comprehensive genomic landscape of 16 MRT xenograft models using whole-genome sequencing (WGS), transcriptome profiling (RNAseq), and DNA methylation analysis (EM-seq), representing intracranial (AT/RT; n=6), extracranial (RTK; n=5), and soft tissue subtypes (n=5). This work builds on our previous studies investigating the in-vivo activity of the combination of the PARP1 inhibitor, PEGylated talazoparib (PEG~TLZ), and the DNA alkalyating agent, temozolomide (TMZ), in MRTs, as well as the associated transcriptional changes underlying therapeutic response. WGS analysis revealed recurrent mutations in TP53 , BRCA1 , and BRCA2 genes across tumors, regardless of tumor demographics. All 16 MRT tumors harbored SMARCB1 alterations, including single-nucleotide variants, whole or partial gene deletion, and/or loss of heterozygosity (LOH). Consistently, LOH was confirmed in 15 of 16 tumors. Differential expression analyses identified elevated activity of Receptor Tyrosine Kinase (RTK), Ephrin, and Epidermal Growth Factor Receptor (EGFR) signaling pathways in good responders (maintained/complete response) compared with poor responders (partial response or progressive disease) across treatment groups (PEG~TLZ, TMZ, and the combination), as reported previously. RNAseq further detected several gene fusions , one of which was experimentally validated. Supervised clustering of EM-seq data revealed a characteristic binary methylation pattern independent of tissue origin. Differential methylation analysis of promoter CpG islands identified 5 genes exhibiting a strong inverse correlation between DNA methylation and mRNA expression, highlighting potential therapeutic targets whose activity may be modulated via epigenetic mechanisms. Overall, our comprehensive multi-omics characterization of these ultra-rare MRTs establishes a foundational and enduring resource for the pediatric cancer research community. By providing deeply annotated genomic, transcriptomic, and epigenomic profiles across diverse MRT subtypes, this dataset will support long-term mechanistic studies, enable identification of therapeutic vulnerabilities, and help guide the development of future clinical strategies for this highly aggressive pediatric cancer.