Deconstructing Sonic Hedgehog Medulloblastoma: Molecular Subtypes, Drivers, and Beyond

Medulloblastoma (MB) is a highly malignant cerebellar tumor predominantly diagnosed during childhood. Driven by pathogenic activation of sonic hedgehog (SHH) signaling, SHH subgroup MB (SHH-MB) accounts for nearly one-third of diagnoses. Extensive molecular analyses have identified biologically and clinically relevant intertumoral heterogeneity among SHH-MB tumors, prompting the recognition of novel subtypes. Beyond germline and somatic mutations promoting constitutive SHH signaling, driver alterations affect a multitude of pathways and molecular processes, including TP53 signaling, chromatin modulation, and post-transcriptional gene regulation. Here, we review recent advances in the underpinnings of SHH-MB in the context of molecular subtypes, clarify novel somatic and germline drivers, highlight cellular origins and developmental hierarchies, and describe the composition of the tumor microenvironment and its putative role in tumorigenesis. SHH-MBs are characterized by pathogenic activation of SHH signaling. Continued exploration of the somatic and germline molecular landscapes have revealed alterations in a variety of functional processes, including chromatin modulation and post-transcriptional gene regulation.Intertumoral heterogeneity amongst SHH-MB subgroup tumors has been described in terms of molecular subtypes (α, β, γ, and δ) with distinctive patient demographics, genetic lesions, and clinical outcomes.Developmental origins of SHH-MB have been pinpointed to the GN lineage with age-associated distinctions in cellular and differentiation hierarchies.Over 40% of pediatric SHH-MBs exhibit damaging germline mutations, while such events are much rarer among adults.Quiescent, therapy-resistant cells, such as SOX2+ and OLIG2+ progenitor cells, may serve as reservoirs for tumor regrowth in relapsed SHH-MB. Divergent clonal selection may drive recurrence through selective pressures imposed by therapy.