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Publication : Divergent clonal selection dominates medulloblastoma at recurrence.

First Author  Morrissy AS Year  2016
Journal  Nature Volume  529
Issue  7586 Pages  351-7
PubMed ID  26760213 Mgi Jnum  J:241192
Mgi Id  MGI:5897966 Doi  10.1038/nature16478
Citation  Morrissy AS, et al. (2016) Divergent clonal selection dominates medulloblastoma at recurrence. Nature 529(7586):351-7
abstractText  The development of targeted anti-cancer therapies through the study of cancer genomes is intended to increase survival rates and decrease treatment-related toxicity. We treated a transposon-driven, functional genomic mouse model of medulloblastoma with 'humanized' in vivo therapy (microneurosurgical tumour resection followed by multi-fractionated, image-guided radiotherapy). Genetic events in recurrent murine medulloblastoma exhibit a very poor overlap with those in matched murine diagnostic samples (<5%). Whole-genome sequencing of 33 pairs of human diagnostic and post-therapy medulloblastomas demonstrated substantial genetic divergence of the dominant clone after therapy (<12% diagnostic events were retained at recurrence). In both mice and humans, the dominant clone at recurrence arose through clonal selection of a pre-existing minor clone present at diagnosis. Targeted therapy is unlikely to be effective in the absence of the target, therefore our results offer a simple, proximal, and remediable explanation for the failure of prior clinical trials of targeted therapy.
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