Abstract 3436: Pan-cancer analysis of the HIF-transcriptional pathway and its association with genetic susceptibility to cancer
Authors: Mole David R. , Schmid Virginia , Lombardi Olivia , Halim Silvia , Lafleur Veronique N. , Li Ran , Salama Rafik , Colli Leandro , Chanock Stephen , Ratcliffe Peter J. 
Published: September 2020

Abstract
The purpose of this study was to determine whether specific components of the HIF-transcriptional pathway are under selective pressure during the development of cancer. Induction of HIF is a common feature of most cancers that frequently results from intra-tumour hypoxia but may also be activated as a result of oncogenic switching. Activation of such large transcriptional pathways commonly leads to heterogeneous effects on tumour biology that entrain multiple responses, which both promote and inhibit tumour formation. This generates a Darwinian pressure that selects for variants (either germline or somatic) that re-balance the numerous (often small) opposing effects of pathway activation to promote tumourigenesis. We have undertaken pangenomic analyses of the direct and indirect transcriptional targets of the HIF pathway in cell lines from six common cancer types (breast, prostate, lung, colon, kidney and liver) using combined ChIP-seq and RNA-seq assays. This identifies a small set of common HIF-target genes affecting discrete pathways as well as much larger sets of target genes that are cancer-type specific. Correlating these findings with RNA-seq analyses across 20 tumour types in the TCGA database confirms distinct patterns of expression and the importance of these genes to tumour biology. Furthermore, by relating our datasets to GWAS signals of cancer-susceptibility in each tumour type, we have identified a significant excess overlap between cancer-susceptibility loci and HIF-target genes. Notably, despite the importance of HIF in other tumour types, this overlap is specific to kidney cancer in which, by contrast, HIF activation, resulting from oncogenic switching, is inappropriate to the level of intra-tumour oxygenation. This analysis provides a comprehensive analysis of the HIF pathway across multiple cancer types and provides evidence that specific aspects of the HIF-pathway are under Darwinian selection in kidney cancer. Since these alter kidney cancer susceptibility, this analysis helps distinguish those components of the HIF transcriptional response that drive tumour formation from those that are simply co-activated as a consequence of large-pathway activation. Finally, this work supports a ‘pathway tuning' model of cancer and suggests that subtle re-balancing of inappropriately activated, cancer-specific pathways is important in oncogenesis.
Citation Format: David R. Mole, Virginia Schmid, Olivia Lombardi, Silvia Halim, Veronique N. Lafleur, Ran Li, Rafik Salama, Leandro Colli, Stephen Chanock, Peter J. Ratcliffe. Pan-cancer analysis of the HIF-transcriptional pathway and its association with genetic susceptibility to cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3436.