Divergent clonal selection dominates medulloblastoma at recurrence

Article

关键词: EVOLUTION;    HETEROGENEITY;    MUTATIONS;    DYNAMICS;    IMPACT;    MUTAGENESIS;    SUBGROUPS;    INFERENCE;    RELAPSE;    CELLS;   

DOI  :  10.1038/nature16478

来源: SCIE

【 摘 要 】

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.

【 授权许可】

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