4.5 Article

Pan-cancer analysis of advanced patient tumors reveals interactions between therapy and genomic landscapes

Journal

NATURE CANCER
Volume 1, Issue 4, Pages 452-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s43018-020-0050-6

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Funding

  1. BC Cancer Foundation
  2. Genome British Columbia [B20POG]
  3. Genome BC [202SEQ, 212SEQ, 12002 GBC]
  4. Canada Foundation for Innovation [20070, 30981, 30198, 33408]
  5. CGEn platform [35444]
  6. BC Knowledge Development Fund
  7. Canadian Institutes of Health Research Foundation Grants program [FDN 143288]
  8. University of British Columbia Clinician Investigator Program
  9. Canadian Institutes of Health Research Vanier Canada Graduate Scholarship
  10. Common Fund of the Office of the Director of the National Institutes of Health

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Advanced and metastatic tumors with complex treatment histories drive cancer mortality. Here we describe the POG570 cohort, a comprehensive whole-genome, transcriptome and clinical dataset, amenable for exploration of the impacts of therapies on genomic landscapes. Previous exposure to DNA-damaging chemotherapies and mutations affecting DNA repair genes, including POLQ and genes encoding Pol zeta, were associated with genome-wide, therapy-induced mutagenesis. Exposure to platinum therapies coincided with signatures SBS31 and DSB5 and, when combined with DNA synthesis inhibitors, signature SBS17b. Alterations in ESR1, EGFR, CTNNB1, FGFR1, VEGFA and DPYD were consistent with drug resistance and sensitivity. Recurrent noncoding events were found in regulatory region hotspots of genes including TERT, PLEKHS1, AP2A1 and ADGRG6. Mutation burden and immune signatures corresponded with overall survival and response to immunotherapy. Our data offer a rich resource for investigation of advanced cancers and interpretation of whole-genome and transcriptome sequencing in the context of a cancer clinic.

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