How Low Oxygen Drives Tumours
Landmark pan-cancer study analyzes mutation signatures of low oxygen in thousands of tumours
University of Toronto researchers have discovered the genetic underpinnings of hypoxia – the low oxygen state that surrounds cancer tumours and helps them to grow and resist treatment.
Some tumours thrive in low-oxygen environments, but until now, the reasons for this have been poorly understood. The researchers discovered key molecular hallmarks of hypoxia in the first-ever pan-cancer analysis of low oxygen in human tumours, with a special focus on prostate cancer.
The study, published in Nature Genetics, investigated more than 8,000 human tumours across 19 different cancer types. Researchers discovered common features of hypoxic tumours that could help predict cancer aggressiveness and inform treatment decisions.
These findings, which include several genes more commonly mutated in hypoxic cancers and new information about hypoxia-related patterns of tumour evolution, make up the largest resource available for hypoxia research.
“If we look at any single aspect of cancer, we only gain a partial understanding of this complex disease. But here we’ve exploited a wealth of human tumour data to gain a more comprehensive understanding,” says lead author Vinayak Bhandari, a researcher at the Ontario Institute for Cancer Research and PhD candidate in Medical Biophysics at U of T. “By tying together our new understanding of the environment in which tumours develop with detailed evaluation of genetic changes, we created a biological signature that highlights patients who may benefit from more therapy.”
The markers discovered in this study also open new opportunities for researchers to develop therapies that target hypoxia-related treatment resistance and metastasis across many types of cancer, including prostate cancer.
“Understanding common genomic traits across cancer types is critically important to the future of cancer diagnosis and treatment,” says co-author Paul Boutros, formerly of the departments of Medical Biophysics and Pharmacology and Toxicology, and now at the University of California, Los Angeles. “We were initially motivated by the inability to differentiate between aggressive and non-aggressive prostate cancers, but our findings now provide insights into how treatments might be developed for many tumour types.”
“Hypoxia was preveiously associated with aggressive disease, but the mechanisms by which it’s drives this process in human tumours was poorly understood from a genetic angle, “ says co-author Robert Bristow, formerly a professor in the departments of Medical Biophysics and Radiation Oncology at U of T, and now at the University of Manchester. “We can now start to exploit these findings into novel clinical trials to target hypoxia and abnormal genetics at the same time.”
The study was supported by the Movember Foundation, Prostate Cancer Canada and OICR through CPC-GENE – the largest prostate cancer genomics project in the world. The project was also funded by the Terry Fox Research Institute. Tumour sample data was provided by CPC-GENE, the International Cancer Genome Consortium and The Cancer Genome Atlas project.
With files from Hal Coiste, Ontario Cancer Research Institute
