Molecular landmarks of tumour hypoxia across cancer types 

Many primary-tumour subregions have low levels of molecular oxygen, termed hypoxia. Hypoxic tumours are at elevated risk for local failure and distant metastasis, but the molecular hallmarks of tumour hypoxia remain poorly defined.

To fill this gap, we quantified hypoxia in 8,006 tumours across 19 tumour types. In ten tumour types, hypoxia was associated with elevated genomic instability. In all 19 tumour types, hypoxic tumours 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 localised 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 tumour nimbosus, an aggressive cellular phenotype.

Overall, this work establishes that tumour hypoxia may drive aggressive molecular features across cancers and shape the clinical trajectory of individual tumours.