Molecular landmarks of tumor hypoxia across cancer types

• Published in: Nature genetics Vol. 51; no. 2; pp. 308 - 318
• Main Authors: Bhandari, Vinayak, Hoey, Christianne, Liu, Lydia Y., Lalonde, Emilie, Ray, Jessica, Livingstone, Julie, Lesurf, Robert, Shiah, Yu-Jia, Vujcic, Tina, Huang, Xiaoyong, Espiritu, Shadrielle M. G., Heisler, Lawrence E., Yousif, Fouad, Huang, Vincent, Yamaguchi, Takafumi N., Yao, Cindy Q., Sabelnykova, Veronica Y., Fraser, Michael, Chua, Melvin L. K., van der Kwast, Theodorus, Liu, Stanley K., Boutros, Paul C., Bristow, Robert G.
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.02.2019; Nature Publishing Group
• Subjects: 38; 45; 45/23; 45/61; 45/91; 631/208/212/2166; 631/67/1857; 631/67/327; 631/67/589; Agriculture; Analysis; Animal Genetics and Genomics; Anoxia; Automation; Bioinformatics; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer metastasis; Cancer Research; Chromosomes; Constellations; Deoxyribonucleic acid; Discovery tools; DNA; Gene expression; Gene Function; Gene mutation; Genomes; Genomic instability; Human Genetics; Hypoxia; Metabolism; Metastases; MicroRNA; miRNA; Mutation; Ovarian cancer; Oxygen; Phenotypes; Prostate cancer; PTEN protein; Stability; Telomeres; Thyroid gland; Tumors
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-018-0318-2

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.