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.

中文翻译：

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跨癌症类型的肿瘤缺氧的分子标志。

许多原发性肿瘤亚区域的分子氧水平较低，称为缺氧。低氧性肿瘤发生局部衰竭和远处转移的风险较高，但肿瘤缺氧的分子标志仍然不清楚。为了填补这一空白，我们对19种肿瘤类型中的8,006种肿瘤中的缺氧进行了量化。在十种肿瘤类型中，缺氧与基因组不稳定增加有关。在所有19种肿瘤类型中，低氧性肿瘤均表现出特征性的驱动程序突变特征。我们观察到跨癌症广泛存在的与低氧相关的microRNA（miRNA）失调，并在功能上验证了miR-133a-3p作为低氧调节的miRNA。在局限性前列腺癌中，缺氧与染色体毛发生率升高，PTEN等位基因缺失和端粒缩短有关。这些关联在多克隆肿瘤中特别丰富，代表了类似于肿瘤ni的特征星座，这是一种侵略性细胞表型。总的来说，这项工作确定了肿瘤缺氧可能会驱动各种癌症的侵袭性分子特征，并塑造单个肿瘤的临床轨迹。