Molecular landmarks of tumor hypoxia across cancer types
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...
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| Published in | Nature genetics Vol. 51; no. 2; pp. 308 - 318 |
|---|---|
| Main Authors | , , , , , , , , , , , , , , , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
New York
Nature Publishing Group US
01.02.2019
Nature Publishing Group |
| Subjects | |
| Online Access | Get full text |
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| 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.
Analysis of signatures of hypoxia in more than 8,000 tumors from 19 cancer types identifies hypoxia-driven mutation signatures and dysregulation of microRNAs. |
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| AbstractList | 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. 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. Analysis of signatures of hypoxia in more than 8,000 tumors from 19 cancer types identifies hypoxia-driven mutation signatures and dysregulation of microRNAs. 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. Analysis of signatures of hypoxia in more than 8,000 tumors from 19 cancer types identifies hypoxia-driven mutation signatures and dysregulation of microRNAs. |
| Audience | Academic |
| Author | Huang, Xiaoyong Lesurf, Robert Liu, Stanley K. Bristow, Robert G. Yao, Cindy Q. Boutros, Paul C. Lalonde, Emilie Sabelnykova, Veronica Y. Espiritu, Shadrielle M. G. Liu, Lydia Y. Huang, Vincent Ray, Jessica van der Kwast, Theodorus Shiah, Yu-Jia Fraser, Michael Yousif, Fouad Livingstone, Julie Chua, Melvin L. K. Bhandari, Vinayak Vujcic, Tina Heisler, Lawrence E. Yamaguchi, Takafumi N. Hoey, Christianne |
| Author_xml | – sequence: 1 givenname: Vinayak orcidid: 0000-0003-0265-0835 surname: Bhandari fullname: Bhandari, Vinayak organization: Department of Medical Biophysics, University of Toronto, Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 2 givenname: Christianne orcidid: 0000-0002-9054-4049 surname: Hoey fullname: Hoey, Christianne organization: Department of Medical Biophysics, University of Toronto, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre – sequence: 3 givenname: Lydia Y. surname: Liu fullname: Liu, Lydia Y. organization: Department of Medical Biophysics, University of Toronto, Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 4 givenname: Emilie surname: Lalonde fullname: Lalonde, Emilie organization: Department of Medical Biophysics, University of Toronto, Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 5 givenname: Jessica orcidid: 0000-0002-5413-4739 surname: Ray fullname: Ray, Jessica organization: Department of Medical Biophysics, University of Toronto, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre – sequence: 6 givenname: Julie orcidid: 0000-0002-8424-3768 surname: Livingstone fullname: Livingstone, Julie organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 7 givenname: Robert surname: Lesurf fullname: Lesurf, Robert organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 8 givenname: Yu-Jia orcidid: 0000-0003-4989-2794 surname: Shiah fullname: Shiah, Yu-Jia organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 9 givenname: Tina surname: Vujcic fullname: Vujcic, Tina organization: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre – sequence: 10 givenname: Xiaoyong surname: Huang fullname: Huang, Xiaoyong organization: Sunnybrook Research Institute, Sunnybrook Health Sciences Centre – sequence: 11 givenname: Shadrielle M. G. surname: Espiritu fullname: Espiritu, Shadrielle M. G. organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 12 givenname: Lawrence E. surname: Heisler fullname: Heisler, Lawrence E. organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 13 givenname: Fouad surname: Yousif fullname: Yousif, Fouad organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 14 givenname: Vincent orcidid: 0000-0002-6504-179X surname: Huang fullname: Huang, Vincent organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 15 givenname: Takafumi N. orcidid: 0000-0003-1082-3871 surname: Yamaguchi fullname: Yamaguchi, Takafumi N. organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 16 givenname: Cindy Q. surname: Yao fullname: Yao, Cindy Q. organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 17 givenname: Veronica Y. surname: Sabelnykova fullname: Sabelnykova, Veronica Y. organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 18 givenname: Michael surname: Fraser fullname: Fraser, Michael organization: Informatics and Biocomputing Program, Ontario Institute for Cancer Research – sequence: 19 givenname: Melvin L. K. surname: Chua fullname: Chua, Melvin L. K. organization: Division of Radiation Oncology, National Cancer Centre Singapore, Duke–NUS Graduate Medical School – sequence: 20 givenname: Theodorus surname: van der Kwast fullname: van der Kwast, Theodorus organization: Laboratory Medicine Program, University Health Network – sequence: 21 givenname: Stanley K. orcidid: 0000-0001-6851-0857 surname: Liu fullname: Liu, Stanley K. organization: Department of Medical Biophysics, University of Toronto, Sunnybrook Research Institute, Sunnybrook Health Sciences Centre, Department of Radiation Oncology, University of Toronto – sequence: 22 givenname: Paul C. orcidid: 0000-0003-0553-7520 surname: Boutros fullname: Boutros, Paul C. email: pboutros@mednet.ucla.edu organization: Department of Medical Biophysics, University of Toronto, Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Department of Pharmacology and Toxicology, University of Toronto, Department of Human Genetics, University of California, Los Angeles, Department of Urology, University of California, Los Angeles, Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Institute for Precision Health, University of California, Los Angeles – sequence: 23 givenname: Robert G. orcidid: 0000-0002-8553-9544 surname: Bristow fullname: Bristow, Robert G. email: robert.bristow@manchester.ac.uk organization: Department of Medical Biophysics, University of Toronto, Department of Radiation Oncology, University of Toronto, Princess Margaret Hospital, University Health Network, Toronto, Division of Cancer Sciences, Faculty of Biology, Health and Medicine, University of Manchester, The Christie NHS Foundation Trust, CRUK Manchester Institute and Manchester Cancer Research Centre |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/30643250$$D View this record in MEDLINE/PubMed |
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| Title | Molecular landmarks of tumor hypoxia across cancer types |
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