Longitudinal single-cell and spatial profiling of sonic hedgehog medulloblastoma identifies novel therapeutic targets
Year: 2026
Type: article
Abstract: Background Sonic hedgehog (SHH) medulloblastoma (MB) accounts for approximately one-third of all MB cases, the most common malignant brain tumor in children. Despite therapy, SHH MB relapse is frequent and has a dismal prognosis. New treatments for recurrent SHH MB are needed; however, the molecular drivers of relapse are poorly understood. Methods We profiled 22 SHH MB specimens (16 primary and 6 recurrent), including four primary–recurrent patient pairs, using overlapping single-nucleus RNA sequencing (snRNA-seq; n = 16), single-nucleus assay for transposase-accessible chromatin sequencing (snATAC-seq; n = 13), and spatial transcriptomic ( n = 6) cohorts. We integrated these data with exome-derived variant calls from 25 specimens, including seven patients with primary and recurrent samples. Bulk RNA-seq data from 48 specimens representing 24 primary–recurrent pairs were used for validation. Results Our analyses show evidence of positive selection for nonsynonymous tumor mutations, including TP53 mutations involving its DNA-binding and tetramerization domains. TP53 mutations were associated with reduced base-excision repair (BER) gene expression and accessibility of linked cis-regulatory regions. Recurrent tumors showed increased tumor mutational burden (TMB) and an endoplasmic-reticulum (ER) stress expression program associated with poorer survival. Angiogenic gene expression and inferred immunosuppressive myeloid signaling were increased in recurrent disease. Conclusions These data define recurrence-associated cellular and regulatory programs, nominate candidate therapeutic targets and prognostic markers, and provide a single-cell and spatial atlas of SHH MB.
Source: Genome Medicine
Institutions: University of California, San Francisco, University of Trento
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $5,290
OpenAlex ID: W7222834631
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