Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Informatics and Biocomputing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Nat Genet. 2019 Feb;51(2):308-318. doi: 10.1038/s41588-018-0318-2. Epub 2019 Jan 14.
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.
许多原发肿瘤亚区的分子氧水平较低，称为缺氧。缺氧肿瘤局部复发和远处转移的风险增加，但肿瘤缺氧的分子特征仍未得到很好的定义。为了填补这一空白，我们对 19 种肿瘤类型的 8006 个肿瘤进行了缺氧定量。在十种肿瘤类型中，缺氧与基因组不稳定性升高有关。在所有 19 种肿瘤类型中，缺氧肿瘤表现出特征性的驱动基因突变特征。我们观察到癌症中广泛存在与缺氧相关的 microRNA（miRNA）失调，并对 miR-133a-3p 作为一种受缺氧调节的 miRNA 进行了功能验证。在局限性前列腺癌中，缺氧与染色体重排、PTEN 等位基因丢失和端粒较短的发生率升高有关。这些关联在多克隆肿瘤中尤为丰富，代表了类似于肿瘤云雾状的一组特征，这是一种侵袭性细胞表型。总的来说，这项工作表明，肿瘤缺氧可能会在癌症中驱动侵袭性的分子特征，并影响个体肿瘤的临床进程。
