Journal
NATURE GENETICS
Volume 51, Issue 2, Pages 308-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41588-018-0318-2
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Funding
- Movember funds through Prostate Cancer Canada
- Ontario Institute for Cancer Research
- Movember Foundation [RS2014-01]
- Terry Fox Research Institute New Investigator Award
- Prostate Cancer Canada Rising Star Fellowship
- Canadian Institutes of Health Research (CIHR) New Investigator Award
- Ontario government
- Movember Rising Star award - Movember Foundation [RS2014-03, D2015-12, D2017-1811]
- Telus Motorcycle Ride For Dad
- Ministry of Research and Innovation Early Researcher Award
- Princess Margaret Cancer Centre Foundation
- Terry Fox Research Institute Program Project Grant
- Canadian Cancer Society Research Scientist Award
- CRUK Manchester Institute through Cancer Research UK
- Government of Ontario
- Prostate Cancer Canada
- CIHR
- Radiation Medicine Program Academic Enrichment Fund
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Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumors are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumor hypoxia remain poorly defined. To fill this gap, we quantified hypoxia in 8,006 tumors across 19 tumor types. In ten tumor types, hypoxia was associated with elevated genomic instability. In all 19 tumor types, hypoxic tumors exhibited characteristic driver-mutation signatures. We observed widespread hypoxia-associated dysregulation of microRNAs (miRNAs) across cancers and functionally validated miR-133a-3p as a hypoxia-modulated miRNA. In localized prostate cancer, hypoxia was associated with elevated rates of chromothripsis, allelic loss of PTEN and shorter telomeres. These associations are particularly enriched in polyclonal tumors, representing a constellation of features resembling tumor nimbosus, an aggressive cellular phenotype. Overall, this work establishes that tumor hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumors.
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