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Clonal selection drives genetic divergence of metastatic medulloblastoma.

Nature | Feb 15, 2012

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 cord. 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 system. The mechanisms of dissemination through the cerebrospinal fluid are poorly studied, and medulloblastoma metastases have been assumed to be biologically similar to the primary tumour. 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.

Pubmed ID: 22343890 RIS Download

Mesh terms: Animals | Clonal Evolution | CpG Islands | DNA Methylation | DNA Transposable Elements | Disease Models, Animal | Genes, p53 | Germ-Line Mutation | Humans | Li-Fraumeni Syndrome | Medulloblastoma | Mice | Mutagenesis, Insertional | Neoplasm Metastasis | Survival Rate

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Associated grants

  • Agency: NCI NIH HHS, Id: R01 CA148699-03
  • Agency: NINDS NIH HHS, Id: R01 NS055089
  • Agency: NCI NIH HHS, Id: R01 CA108622
  • Agency: NCI NIH HHS, Id: K01CA122183
  • Agency: NCI NIH HHS, Id: R01 CA113636
  • Agency: Canadian Institutes of Health Research, Id: R56 NS055089
  • Agency: NINDS NIH HHS, Id: R01 CA148699
  • Agency: NCI NIH HHS, Id: K01 CA122183
  • Agency: NCI NIH HHS, Id: R01CA148699
  • Agency: NCI NIH HHS, Id: NS055089
  • Agency: NINDS NIH HHS, Id:

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SAMTOOLS

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QIAGEN

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