Co-incidence of RCC-susceptibility polymorphisms with HIF cis-acting sequences supports a pathway tuning model of cancer
10 December 2019
Virginia Schmid, Veronique N. Lafleur, Olivia Lombardi, Ran Li, Rafik Salama, Leandro Colli, Hani Choudhry, Stephen Chanock, Peter J. Ratcliffe & David R. Mole
Scientific Reports, volume 9, Article number: 18768 (2019)
Emerging evidence suggests that dysregulation of oncogenic pathways requires precise tuning in order for cancer to develop. To test this, we examined the overlap between cis-acting elements of the hypoxia-inducible factor (HIF) pathway and cancer-susceptibility polymorphisms as defined in genome-wide association studies (GWAS). In renal cancer, where HIF is constitutively and un-physiologically activated by mutation of the von Hippel-Lindau tumour suppressor, we observed marked excess overlap, which extended to potential susceptibility polymorphisms that are below the conventional threshold applied in GWAS. In contrast, in other cancers where HIF is upregulated by different mechanisms, including micro-environmental hypoxia, we observed no excess in overlap. Our findings support a ‘pathway tuning’ model of cancer, whereby precise modulation of multiple outputs of specific, activated pathways is important in oncogenesis. This implies that selective pressures to modulate such pathways operate during cancer development and should focus attempts to identify their nature and consequences.
Understanding Causes of Disease
A key research priority will be to use health data in its multiple forms to understand the causes of disease and discover new targeted treatments rather than just addressing symptoms. Led by...
Sir Martin Landray
Professor of Medicine and Epidemiology at the University of Oxford and HDR UK's Science Priority Lead for Clinical Trials
Professor Sir Martin Landray is Professor of Medicine and Epidemiology at the University of Oxford and HDR UK’s Science Priority Lead for Clinical Trials. Martin is also Deputy Director of the...