10779/crick.11689353.v1
Virginia Schmid
Virginia
Schmid
Veronique N Lafleur
Veronique N
Lafleur
Olivia Lombardi
Olivia
Lombardi
Ran Li
Ran
Li
Rafik Salama
Rafik
Salama
Leandro Colli
Leandro
Colli
Hani Choudhry
Hani
Choudhry
Stephen Chanock
Stephen
Chanock
Peter J Ratcliffe
Peter J
Ratcliffe
David R Mole
David R
Mole
Co-incidence of RCC-susceptibility polymorphisms with HIF cis-acting sequences supports a pathway tuning model of cancer.
The Francis Crick Institute
2020
Ratcliffe FC001501
0601 Biochemistry and Cell Biology
0299 Other Physical Sciences
2020-01-22 17:52:09
Journal contribution
https://crick.figshare.com/articles/journal_contribution/Co-incidence_of_RCC-susceptibility_polymorphisms_with_HIF_cis-acting_sequences_supports_a_pathway_tuning_model_of_cancer_/11689353
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.