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Subtypes of medulloblastoma have distinct developmental origins

Abstract

Medulloblastoma encompasses a collection of clinically and molecularly diverse tumour subtypes that together comprise the most common malignant childhood brain tumour1,2,3,4. 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 impact on progenitor cell populations in the cerebellum, but caused the abnormal accumulation of cells on the embryonic dorsal brainstem which included aberrantly proliferating Zic1+ precursor cells. These lesions persisted in all mutant adult mice; moreover, in 15% of cases in which Tp53 was concurrently deleted, they progressed to form medulloblastomas that recapitulated the anatomy and gene expression profiles of human WNT-subtype medulloblastoma. We provide the first evidence, to our knowledge, that subtypes of medulloblastoma have distinct cellular origins. Our data provide an explanation for the marked molecular and clinical differences between SHH- and WNT-subtype medulloblastomas and have profound implications for future research and treatment of this important childhood cancer.

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Figure 1: WNT and SHH subtypes of medulloblastoma are anatomically distinct.
Figure 2: Mutant- Ctnnb1 causes aberrant accumulation of LRL cells.
Figure 3: Mutant- Ctnnb1 and SHH-subtype mouse medulloblastomas are anatomically distinct.
Figure 4: Mutant- Ctnnb1 mouse medulloblastomas recapitulate the molecular characteristics of human WNT-subtype disease.

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Acknowledgements

R.J.G. holds the Howard C. Schott Research Chair from the Malia’s Cord Foundation, and is supported by grants from the National Institutes of Health (R01CA129541, P01CA96832 and P30CA021765), the Collaborative Ependymoma Research Network and by the American Lebanese Syrian Associated Charities. We are grateful to A. Chenn, J. Johnson and C. Birchmeier for their gifts of reagents and the staff of the Hartwell Center for Bioinformatics and Biotechnology and ARC at St Jude Children’s Research Hospital for technical assistance.

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R.J.G. conceived the research and planned experiments. P.G. also planned and conducted most of the experiments. Y.T., G.R., D.S.C., M.C.T., T.H., H.P., J.M., J.C.L., Y.L., F.Z., C.E., S.C.C., M.F.R., P.J.M. and R.W.-R. conducted experiments. D.F. and S.P. provided bioinformatic expertise. A.G., F.A.B. and R.A.S. provided clinical advice and tumour samples. D.H.G. provided the Blbp-Cre mouse and data. M.M.T. provided the Ctnnb1lox(ex3)/lox(ex3) mouse. Z.P. and R.O. reviewed and analysed the human MRI scans. D.W.E. provided pathology review. All authors contributed to writing the manuscript.

Corresponding author

Correspondence to Richard J. Gilbertson.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

The file contains Supplementary Methods, additional references, Supplementary Figures 1-14 with legends and Supplementary Table 1. (PDF 12061 kb)

Supplementary Dataset 1

This dataset reports the expression distribution in the developing mouse hindbrain (rhombomeres 1-8) of 24 and 25 signature genes of human WNT-subgroup and SHH-subgroup medulloblastoma respectfully. (PDF 30323 kb)

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Gibson, P., Tong, Y., Robinson, G. et al. Subtypes of medulloblastoma have distinct developmental origins. Nature 468, 1095–1099 (2010). https://doi.org/10.1038/nature09587

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