Gene

microRNA

Metastasis

Tumor progression

Biology

Prostate cancer

Apoptosis

Cancer research

Hypoxia (environmental)

Chromosome instability

Radiation therapy

Tumor hypoxia

Genetics

PTEN

Organic chemistry

Oxygen

Genome instability

Tumor microenvironment

Tumor cells

Internal medicine

Medicine

Chemistry

DNA damage

PI3K/AKT/mTOR pathway

Cancer

Chromosome

Pathology

Nature Genetics

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. Analysis of signatures of hypoxia in more than 8,000 tumors from 19 cancer types identifies hypoxia-driven mutation signatures and dysregulation of microRNAs.

Molecular landmarks of tumor hypoxia across cancer types