Molecular landmarks of tumor hypoxia across cancer types
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.
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Tumor size and associated hypoxia levels affect tumor aggressiveness.
“recently published literature discusses the role of the size of a tumor (and the associated hypoxia levels) on its aggressiveness [81,82,83,84,85] and on the efficacy of drug delivery to it [84,86,87].”
From The Tumor-on-Chip: Recent Advances in the Development of Microfluidic Systems to Recapitulate the Physiology of Solid Tumors (2019) · cites this paper as [81]
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- Authors
- Bhandari, V., Hoey, C., Liu, L. Y., Lalonde, E., Ray, J., Livingstone, J., Lesurf, R., Shiah, Y.-J., Vujcic, T., Huang, X., Espiritu, S. M. G., Heisler, L. E., Yousif, F., Huang, V., Yamaguchi, T. N., Yao, C. Q., Sabelnykova, V. Y., Fraser, M., Chua, M. L. K., van der Kwast, T., Liu, S. K., Boutros, P. C., & Bristow, R. G.
- Affiliations
- Ontario Institute for Cancer Research (CA)
- Sunnybrook Health Science Centre (CA)
- National University of Singapore (SG)
- University Health Network (CA)
- Corresponding author
- Boutros, Paul C.
- Bristow, Robert G.
- ORCID
- Bhandari, Vinayak
- Hoey, Christianne
- Liu, Lydia Y.
- Lalonde, Emilie
- Ray, Jessica
- Livingstone, Julie
- Lesurf, Robert
- Shiah, Yu-Jia
- Huang, Xiaoyong
- Espiritu, Shadrielle M. G.
- Heisler, Lawrence E.
- Huang, Vincent
- Yamaguchi, Takafumi N.
- Sabelnykova, Veronica Y.
- Fraser, Michael
- Chua, Melvin L. K.
- Liu, Stanley K.
- Boutros, Paul C.
- Bristow, Robert G.
- Venue
- Nature Genetics
- Published
- 2019-01-14
- Volume
- 51
- Issue
- 2
- Pages
- 308-318
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2908755714
- Cited by
- 678
- References
- 11
- Citations by year
- 2026: 42 · 2025: 67 · 2024: 83 · 2023: 128 · 2022: 116 · 2021: 133 · 2020: 80 · 2019: 29
- FWCI
- 28.81
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Gene expression and cancer classification
- Keywords
- tumor hypoxia, genomic instability, driver mutations, microRNA dysregulation, miR-133a-3p, chromothripsis, telomere length, metastasis, prostate cancer, cross-cancer analysis
- MeSH terms
- Tumor Hypoxia, Chromothripsis, PC-3 Cells, Alleles, Hypoxia, Humans, Male, Prostatic Neoplasms, Gene Expression Regulation, Neoplastic, Telomere, Gene Expression Profiling, MicroRNAs, Genomic Instability, Cell Line, Tumor, PTEN Phosphohydrolase
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