Molecular landmarks of tumor hypoxia across cancer types

doi:10.1038/s41588-018-0318-2

. 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

Vinayak Bhandari^{1

2}, Christianne Hoey^{1

3}, Lydia Y Liu^{1

2}, Emilie Lalonde^{1

2}, Jessica Ray^{1

3}, Julie Livingstone², Robert Lesurf², Yu-Jia Shiah², Tina Vujcic³, Xiaoyong Huang³, Shadrielle M G Espiritu², Lawrence E Heisler², Fouad Yousif², Vincent Huang², Takafumi N Yamaguchi², Cindy Q Yao², Veronica Y Sabelnykova², Michael Fraser², Melvin L K Chua^{4

5}, Theodorus van der Kwast⁶, Stanley K Liu^{1

3

7}, Paul C Boutros^{8

9

10

11

12

13

14}, Robert G Bristow^{15

16

17

18

19

20}

Affiliations

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.

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

Molecular landmarks of tumor hypoxia across cancer types

Vinayak Bhandari et al. Nat Genet. 2019 Feb.

. 2019 Feb;51(2):308-318.

doi: 10.1038/s41588-018-0318-2. Epub 2019 Jan 14.

Authors

Affiliations

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.

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

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.

PubMed Disclaimer

Comment in

Hypoxic Tumors Share Genomic Instability.
[No authors listed] [No authors listed] Cancer Discov. 2019 Mar;9(3):314. doi: 10.1158/2159-8290.CD-NB2019-012. Epub 2019 Feb 5. Cancer Discov. 2019. PMID: 30723077

Cited by

Resistance of Hypoxic Cells to Ionizing Radiation Is Mediated in Part via Hypoxia-Induced Quiescence.
Menegakis A, Klompmaker R, Vennin C, Arbusà A, Damen M, van den Broek B, Zips D, van Rheenen J, Krenning L, Medema RH. Menegakis A, et al. Cells. 2021 Mar 10;10(3):610. doi: 10.3390/cells10030610. Cells. 2021. PMID: 33801903 Free PMC article.
Construction of brain metastasis prediction model in limited stage small cell lung cancer patients without prophylactic cranial irradiation.
Guo J, Liu J, Ye W, Xu J, Zhong W, Zhang X, Yuan H, Shi H, Li T, Xu Y, Mao J, Shen B, Wu D. Guo J, et al. Clin Respir J. 2024 Jan;18(1):e13730. doi: 10.1111/crj.13730. Clin Respir J. 2024. PMID: 38286746 Free PMC article.
Refinement of an Established Procedure and Its Application for Identification of Hypoxia in Prostate Cancer Xenografts.
Elming PB, Wittenborn TR, Busk M, Sørensen BS, Thomsen MBH, Strandgaard T, Dyrskjøt L, Nielsen S, Horsman MR. Elming PB, et al. Cancers (Basel). 2021 May 26;13(11):2602. doi: 10.3390/cancers13112602. Cancers (Basel). 2021. PMID: 34073301 Free PMC article.
Role of MicroRNA in Hypoxic Tumours and their Potential as Biomarkers for Early Detection of Cancer.
Jayashree P, Kalpita M, Judith T, Singh AS, Ashwin K. Jayashree P, et al. Curr Mol Med. 2024;24(5):525-536. doi: 10.2174/0115665240268661231128094831. Curr Mol Med. 2024. PMID: 38310548 Review.
Oscillations and Dynamic Symbiosis in Cellular Metabolism in Cancer.
Amemiya T, Yamaguchi T. Amemiya T, et al. Front Oncol. 2022 Feb 16;12:783908. doi: 10.3389/fonc.2022.783908. eCollection 2022. Front Oncol. 2022. PMID: 35251968 Free PMC article.

See all "Cited by" articles

Publication types

Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
Other Literature Sources
- The Lens - Patent Citations Database
Medical
- MedlinePlus Health Information
Research Materials
- NCI CPTC Antibody Characterization Program
Miscellaneous
- NCI CPTAC Assay Portal

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Molecular landmarks of tumor hypoxia across cancer types

Affiliations

Molecular landmarks of tumor hypoxia across cancer types

Authors

Affiliations

Abstract

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous

Abstract

Comment in

Similar articles

Cited by

Publication types

MeSH terms

Substances

Related information

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Research Materials

Miscellaneous