Clonal selection drives genetic divergence of metastatic medulloblastoma

Abstract

Medulloblastoma, the most common malignant paediatric brain tumour, arises in the cerebellum and disseminates through the cerebrospinal fluid in the leptomeningeal space to coat the brain and spinal cord1. Dissemination, a marker of poor prognosis, is found in up to 40% of children at diagnosis and in most children at the time of recurrence. Affected children therefore are treated with radiation to the entire developing brain and spinal cord, followed by high-dose chemotherapy, with the ensuing deleterious effects on the developing nervous system2. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour3,4. Here we show that in both mouse and human medulloblastoma, the metastases from an individual are extremely similar to each other but are divergent from the matched primary tumour. Clonal genetic events in the metastases can be demonstrated in a restricted subclone of the primary tumour, suggesting that only rare cells within the primary tumour have the ability to metastasize. Failure to account for the bicompartmental nature of metastatic medulloblastoma could be a major barrier to the development of effective targeted therapies.

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Figure 1: Transposon mutagenesis models of disseminated human medulloblastoma.
Figure 2: Transposon-driven metastatic medulloblastoma genetically differs from the primary tumour.
Figure 3: Human medulloblastoma metastases are biologically distinct from their matched primary tumour.
Figure 4: Human medulloblastoma metastases are genetically distinct from their matched primary tumour.

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Gene Expression Omnibus

Data deposits

CpG methylation data have been deposited in the Gene Expression Omnibus under accession number GSE34356. Reprints and permissions information is available at www.nature.com/reprints.

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Acknowledgements

M.D.T. holds a Canadian Institutes of Health Research Clinician-Scientist Phase II Award, was a Sontag Foundation Distinguished Scholar, and is supported by grants from the National Institutes of Health (R01CA148699), the Pediatric Brain Tumor Foundation, the Canadian Cancer Society, and Brainchild. X.W. was supported by a fellowship from the American Brain Tumor Association in tribute to Tracy Greenwood. L.G. was supported by a fellowship from the Davis M. Ferguson Fund from the American Brain Tumor Association. A.D. was supported by a Vanier Doctoral Fellowship from the Canadian Institutes of Health Research. L.S.C. was supported by a grant (K01CA122183) and a Kimmel Scholar award from the Kimmel Foundation. C.E. was supported by a grant from the National Institutes of Health (NS055089). We thank S. Archer for technical writing assistance.

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M.D.T., X.W., P.A.N., L.S.C., A.D. and D.L. conceived the research and planned the experiments. X.W., P.A.N., A.D., L.G. and D.J.H.S. carried out the vast majority of the experiments under M.D.T.’s guidance. C.E., T.V.M., D.Z., Y.-J.C., T.M., X.-N.L., V.P.C., M.G.M. and W.A.W. provided human tumour materials. All authors contributed experimental expertise and participated in the writing of the manuscript. A.J.D., D.J.H.S., T.E.S., S.W.S., K.A., J.K., A.L.S., D.L. and L.S.C. provided biostatistical and bioinformatic expertise. E.B. provided the clinical data and analysis. D.W.F. carried out the Akt experiments. N.J., J.S. and J.M. carried out the exome sequencing. H.W., S.M.P. and A.K. carried out the immunostaining of human medulloblastoma tissue microarrays and FISH for MYCN and MYC. S.C. carried out the pathological analysis of mouse brain tumours.

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Correspondence to Michael D. Taylor.

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The authors declare no competing financial interests.

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Wu, X., Northcott, P., Dubuc, A. et al. Clonal selection drives genetic divergence of metastatic medulloblastoma. Nature 482, 529–533 (2012). https://doi.org/10.1038/nature10825

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