van der Kwast, T
Bristow, Robert G
AffiliationDepartment of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
MetadataShow full item record
AbstractMany 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.
CitationBhandari 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.
- Divergent mutational processes distinguish hypoxic and normoxic tumours.
- Authors: Bhandari V, Li CH, Bristow RG, Boutros PC, PCAWG Consortium.
- Issue date: 2020 Feb 5
- A Prostate Cancer "Nimbosus": Genomic Instability and SChLAP1 Dysregulation Underpin Aggression of Intraductal and Cribriform Subpathologies.
- Authors: Chua MLK, Lo W, Pintilie M, Murgic J, Lalonde E, Bhandari V, Mahamud O, Gopalan A, Kweldam CF, van Leenders GJLH, Verhoef EI, Hoogland AM, Livingstone J, Berlin A, Dal Pra A, Meng A, Zhang J, Orain M, Picard V, Hovington H, Bergeron A, Lacombe L, Fradet Y, Têtu B, Reuter VE, Fleshner N, Fraser M, Boutros PC, van der Kwast TH, Bristow RG
- Issue date: 2017 Nov
- Combined MYC Activation and Pten Loss Are Sufficient to Create Genomic Instability and Lethal Metastatic Prostate Cancer.
- Authors: Hubbard GK, Mutton LN, Khalili M, McMullin RP, Hicks JL, Bianchi-Frias D, Horn LA, Kulac I, Moubarek MS, Nelson PS, Yegnasubramanian S, De Marzo AM, Bieberich CJ
- Issue date: 2016 Jan 15
- Hypoxia-Related Tumor Acidosis Affects MicroRNA Expression Pattern in Prostate and Breast Tumor Cells.
- Authors: Riemann A, Reime S, Thews O
- Issue date: 2017
- Hypoxic Lung-Cancer-Derived Extracellular Vesicle MicroRNA-103a Increases the Oncogenic Effects of Macrophages by Targeting PTEN.
- Authors: Hsu YL, Hung JY, Chang WA, Jian SF, Lin YS, Pan YC, Wu CY, Kuo PL
- Issue date: 2018 Feb 7