WNT-activated medulloblastoma

Medulloblastoma was split into four molecular groups by gene-expression studies between 2006 and 2012, and the WHO classification adopted them in 2016. WNT-activated tumours carry an activating CTNNB1 (beta-catenin) mutation in about 90 percent, with monosomy 6 in most and germline APC mutations (Turcot syndrome) in some of the rest; nuclear beta-catenin on immunohistochemistry is the practical marker and DNA methylation profiling the reference test. They arise not from the cerebellar granule cell lineage but from the lower rhombic lip of the brainstem, so they sit in the midline against the brainstem and cerebellar peduncle, have classic histology, occur in children over seven and in adolescents, and are almost never metastatic at diagnosis.

WNT patients treated on the average-risk regimens of the 2000s, 23.4 Gy craniospinal radiotherapy with a posterior fossa or tumour-bed boost followed by cisplatin, vincristine and cyclophosphamide or lomustine, almost all survived: pooled analyses of the SIOP PNET3 and HIT-SIOP PNET4 cohorts and the St Jude SJMB03 trial each found WNT tumours to have the best outcome of any group, with few if any relapses. Because the cost of that therapy in a ten-year-old is intellectual decline, hearing loss, growth and hormone failure and second tumours, both cooperative groups opened de-escalation trials: SJMB12 gives WNT patients 15 Gy craniospinal radiotherapy with a reduced boost and four rather than seven cycles of chemotherapy, and COG ACNS1422 gives 18 Gy craniospinal radiotherapy with reduced chemotherapy for non-metastatic WNT tumours with no residual disease. Both are single-arm studies judged against the historical rate.

The open questions are whether radiotherapy can be cut further, or omitted in favour of chemotherapy alone in the youngest patients; how to treat the rare metastatic or adult WNT tumour, which may not share the excellent prognosis; and whether the mutant beta-catenin pathway itself can be drugged, since no WNT inhibitor has reached the clinic in this disease. Because WNT tumours invade the brainstem, surgeons are advised against chasing the last few millimetres of tumour: residual disease under 1.5 square centimetres does not worsen outcome and brainstem injury does.