期刊
NATURE COMMUNICATIONS
卷 7, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms11111
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资金
- Genomic Medicine and Cancer Themes of the Oxford NIHR Comprehensive Biomedical Research Centre
- Oxford Experimental Cancer Medicine Centre, Cancer Research UK Programme Grant
- EU Horizon 2020 Senior Investigator award (EVOCAN)
- Wellcome Trust [090532/Z/09/Z]
- Academy of Medical Sciences (AMS) [AMS-CSF4-Church] Funding Source: researchfish
- Cancer Research UK [8971] Funding Source: researchfish
- National Institute for Health Research [CL-2010-13-007] Funding Source: researchfish
How chemotherapy affects carcinoma genomes is largely unknown. Here we report whole-exome and deep sequencing of 30 paired oesophageal adenocarcinomas sampled before and after neo-adjuvant chemotherapy. Most, but not all, good responders pass through genetic bottlenecks, a feature associated with higher mutation burden pre-treatment. Some poor responders pass through bottlenecks, but re-grow by the time of surgical resection, suggesting a missed therapeutic opportunity. Cancers often show major changes in driver mutation presence or frequency after treatment, owing to outgrowth persistence or loss of sub-clones, copy number changes, polyclonality and/or spatial genetic heterogeneity. Post-therapy mutation spectrum shifts are also common, particularly C4A and TT4CT changes in good responders or bottleneckers. Post-treatment samples may also acquire mutations in known cancer driver genes (for example, SF3B1, TAF1 and CCND2) that are absent from the paired pre-treatment sample. Neo-adjuvant chemotherapy can rapidly and profoundly affect the oesophageal adenocarcinoma genome. Monitoring molecular changes during treatment may be clinically useful.
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