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    Molecular landmarks of tumor hypoxia across cancer types.

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    Authors
    Bhandari, V
    Hoey, C
    Liu, LY
    Lalonde, E
    Ray, J
    Livingstone, J
    Lesurf, R
    Shiah, YJ
    Vujcic, T
    Huang, X
    Espiritu, SMG
    Heisler, LE
    Yousif, F
    Huang, V
    Yamaguchi, TN
    Yao, CQ
    Sabelnykova, VY
    Fraser, M
    Chua, MLK
    van der Kwast, T
    Liu, SK
    Boutros, PC
    Bristow, Robert G
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    Affiliation
    Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
    Issue Date
    2019
    
    Metadata
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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.
    Citation
    Bhandari V, Hoey C, Liu LY, Lalonde E, Ray J, Livingstone J, et al. Molecular landmarks of tumor hypoxia across cancer types. Nat Genet. 2019 Feb;51(2):308-18.
    Journal
    Nature Genetics
    URI
    http://hdl.handle.net/10541/621602
    DOI
    10.1038/s41588-018-0318-2
    PubMed ID
    30643250
    Additional Links
    https://dx.doi.org/10.1038/s41588-018-0318-2
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1038/s41588-018-0318-2
    Scopus Count
    Collections
    All Paterson Institute for Cancer Research

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