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Divergent clonal selection dominates medulloblastoma at recurrence
Nature (London), 2016-01, Vol.529 (7586), p.351-357
2016
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Autor(en) / Beteiligte
Titel
Divergent clonal selection dominates medulloblastoma at recurrence
Ist Teil von
  • Nature (London), 2016-01, Vol.529 (7586), p.351-357
Ort / Verlag
England: Nature Publishing Group
Erscheinungsjahr
2016
Quelle
MEDLINE
Beschreibungen/Notizen
  • 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.
Sprache
Englisch
Identifikatoren
ISSN: 0028-0836
eISSN: 1476-4687
DOI: 10.1038/nature16478
Titel-ID: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4936195
Format
–
Schlagworte
Animals, Cancer, Cancer therapies, Care and treatment, Cerebellar Neoplasms - genetics, Cerebellar Neoplasms - pathology, Cerebellar Neoplasms - radiotherapy, Cerebellar Neoplasms - surgery, Cerebellar Neoplasms - therapy, Clinical trials, Clonal selection theory, Clone Cells - drug effects, Clone Cells - metabolism, Clone Cells - pathology, Cloning, Craniospinal Irradiation, Cytotoxicity, Disease Models, Animal, DNA Mutational Analysis, Drosophila melanogaster - cytology, Drosophila melanogaster - genetics, Female, Genes, Genetic aspects, Genome, Human - genetics, Genomes, Humans, Male, Medical prognosis, Medulloblastoma, Medulloblastoma - genetics, Medulloblastoma - pathology, Medulloblastoma - radiotherapy, Medulloblastoma - surgery, Medulloblastoma - therapy, Metastasis, Mice, Molecular Targeted Therapy - methods, Mutation, Neoplasm Recurrence, Local - genetics, Neoplasm Recurrence, Local - pathology, Neoplasm Recurrence, Local - therapy, Oncology, Experimental, Radiation therapy, Radiotherapy, Image-Guided, Rodents, Selection, Genetic - drug effects, Signal Transduction, Tumors, Xenograft Model Antitumor Assays

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