Molecular landmarks of tumor hypoxia across cancer types
Molecular landmarks of tumor hypoxia across cancer types
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DOI：
10.1038/s41588-018-0318-2
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发表时间：
2019-02-01
期刊：
影响因子：
30.8
通讯作者：
Bristow, Robert G.
中科院分区：
文献类型：
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作者：
Bhandari, Vinayak;Hoey, Christianne;Bristow, Robert G.
许多原发性肿瘤亚区的分子氧水平较低，称为缺氧。缺氧肿瘤局部衰竭和远处转移的风险增加，但肿瘤缺氧的分子标志仍然定义不清。为了填补这一空白，我们在19种肿瘤类型的8，006个肿瘤中定量了缺氧。在10种肿瘤类型中，缺氧与基因组不稳定性升高相关。在所有19种肿瘤类型中，缺氧肿瘤表现出特征性的驱动突变特征。我们观察到广泛的低氧相关的microRNAs（miRNAs）在癌症和功能验证的miR-133 a-3 p作为低氧调节的miRNA的失调。在局限性前列腺癌中，缺氧与染色体断裂率升高、PTEN等位基因丢失和端粒缩短相关。这些协会是特别丰富的多克隆肿瘤，代表了一个星座的特点，类似肿瘤nimbosus，一个积极的细胞表型。总的来说，这项工作确定了肿瘤缺氧可能会驱动癌症的侵袭性分子特征，并塑造个体肿瘤的临床轨迹。
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.