SHH-activated medulloblastoma

The SHH group arises from cerebellar granule neuron precursors and is defined by activation of the sonic hedgehog pathway: loss of PTCH1 or SUFU, activating SMO mutations, or amplification of GLI2 or MYCN downstream. Age fixes the biology. Infants have PTCH1 or SUFU alterations (germline in a fifth, including Gorlin syndrome), desmoplastic/nodular or extensive-nodularity histology and a good prognosis; adults have PTCH1 and SMO mutations and an intermediate outcome; children aged around eight to seventeen carry TP53 mutations, half of them germline (Li-Fraumeni syndrome), with GLI2 and MYCN amplification and chromothripsis, and do very badly. WHO 2021 therefore splits SHH-activated tumours into TP53-wildtype and TP53-mutant.

The German HIT-SKK'92 trial, reported in the New England Journal of Medicine in 2005, treated infants with cyclophosphamide, vincristine, methotrexate, carboplatin, etoposide and intraventricular methotrexate without radiotherapy and found that desmoplastic histology, which is nearly all SHH, predicted a high cure rate, so radiotherapy-sparing chemotherapy became the infant standard; ACNS1221, which tried to reproduce this without the intraventricular methotrexate, closed early for excess relapses, showing the intraventricular drug matters. For children over three, SHH tumours receive the same craniospinal radiotherapy and chemotherapy as other groups, and TP53-mutant SHH disease relapses despite it: a 2013 pooled analysis found five-year overall survival of 41 percent with a TP53 mutation against 81 percent without in the SHH group. Smoothened inhibitors developed for basal cell carcinoma were tested by the Pediatric Brain Tumor Consortium: vismodegib produced responses only in SHH tumours with upstream PTCH1 or SMO lesions, mostly in adults, that lasted months, and it fuses growth plates in growing children, so it is limited to skeletally mature patients.

Nothing yet helps TP53-mutant SHH disease, which resists radiotherapy and chemotherapy and cannot use SMO inhibitors because its pathway activation is downstream; CDK4/6 inhibitors, bromodomain inhibitors aimed at GLI and MYCN, and immunotherapy are in early trials, and germline TP53 testing at diagnosis matters for the family and for avoiding radiotherapy-induced second tumours. For infants the question is which SHH tumours can be cured with less: SJYC07 and the current SIOP and COG trials stratify by methylation subtype, with high-dose chemotherapy and stem cell rescue kept for the poorer subgroups. Adult SHH medulloblastoma is treated with craniospinal radiotherapy and, increasingly, chemotherapy, with SMO inhibitors reserved for relapse in patients whose tumours carry an upstream mutation.