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Nat Genet. 2019 Feb;51(2):308-318. doi: 10.1038/s41588-018-0318-2. Epub 2019 Jan 14.

Molecular landmarks of tumor hypoxia across cancer types.

Author information

1
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
2
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
3
Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada.
4
Division of Radiation Oncology, National Cancer Centre Singapore, Singapore, Singapore.
5
Duke-NUS Graduate Medical School, Singapore, Singapore.
6
Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
7
Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada.
8
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. pboutros@mednet.ucla.edu.
9
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. pboutros@mednet.ucla.edu.
10
Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada. pboutros@mednet.ucla.edu.
11
Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu.
12
Department of Urology, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu.
13
Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu.
14
Institute for Precision Health, University of California, Los Angeles, Los Angeles, CA, USA. pboutros@mednet.ucla.edu.
15
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. robert.bristow@manchester.ac.uk.
16
Department of Radiation Oncology, University of Toronto, Toronto, Ontario, Canada. robert.bristow@manchester.ac.uk.
17
Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada. robert.bristow@manchester.ac.uk.
18
Division of Cancer Sciences, Faculty of Biology, Health and Medicine, University of Manchester, Manchester, UK. robert.bristow@manchester.ac.uk.
19
The Christie NHS Foundation Trust, Manchester, UK. robert.bristow@manchester.ac.uk.
20
CRUK Manchester Institute and Manchester Cancer Research Centre, Manchester, UK. robert.bristow@manchester.ac.uk.

Abstract

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.

PMID:
30643250
DOI:
10.1038/s41588-018-0318-2

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