Subtypes of medulloblastoma have distinct developmental origins

Medulloblastoma subtypes identified Medulloblastomas, a common type of malignant childhood brain tumour, are thought in the main to arise from the cerebellum, many of them involving aberrant signalling of a signalling pathway involving Sonic Hedgehog. There is substantial heterogeneity among medulloblastomas, however, and new work shows that a distinct subtype of medulloblastoma arises from the dorsal brainstem and is associated with altered Wnt signalling. Distinct molecular and clinical profiles of the subtypes have implications for future treatment. This suggests that subgroups of medulloblastoma are intrinsically different diseases, so therapeutic strategies may need to be tailored accordingly. Medulloblastomas are the most common malignant childhood brain tumours and are thought to arise from the cerebellum. There is substantial heterogeneity among medulloblastomas and some are thought to arise following aberrant Sonic Hedgehog pathway activation. It is now shown that a distinct subtype of medulloblastoma arises from the dorsal brainstem and is associated with altered WNT signalling. Distinct molecular and clinical profiles of the subtypes have implications for future treatment. Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour 1 , 2 , 3 , 4 . These tumours are thought to arise within the cerebellum, with approximately 25% originating from granule neuron precursor cells (GNPCs) after aberrant activation of the Sonic Hedgehog pathway (hereafter, SHH subtype) 3 , 4 , 5 , 6 , 7 , 8 . The pathological processes that drive heterogeneity among the other medulloblastoma subtypes are not known, hindering the development of much needed new therapies. Here we provide evidence that a discrete subtype of medulloblastoma that contains activating mutations in the WNT pathway effector CTNNB1 (hereafter, WNT subtype) 1 , 3 , 4 arises outside the cerebellum from cells of the dorsal brainstem. We found that genes marking human WNT-subtype medulloblastomas are more frequently expressed in the lower rhombic lip (LRL) and embryonic dorsal brainstem than in the upper rhombic lip (URL) and developing cerebellum. Magnetic resonance imaging (MRI) and intra-operative reports showed that human WNT-subtype tumours infiltrate the dorsal brainstem, whereas SHH-subtype tumours are located within the cerebellar hemispheres. Activating mutations in Ctnnb1 had little im