Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway

Grampp S, Schmid V, Salama R, Lauer V, Kranz F, Platt JL, Smythies J, Choudhry H, Goppelt-Strübe M, Ratcliffe PJ, Mole DR, Schoedel J (2017)

Publication Language: English

Publication Type: Journal article

Publication year: 2017

Journal

PLoS Genetics Public Library of Science

Book Volume: 13

Pages Range: e1006872

DOI: 10.1371/journal.pgen.1006872

Abstract

Un-physiological activation of hypoxia inducible factor (HIF) is an early event in most renal cell cancers (RCC) following inactivation of the von Hippel-Lindau tumor suppressor. Despite intense study, how this impinges on cancer development is incompletely understood. To test for the impact of genetic signals on this pathway, we aligned human RCC-susceptibility polymorphisms with genome-wide assays of HIF-binding and observed highly significant overlap. Allele-specific assays of HIF binding, chromatin conformation and gene expression together with eQTL analyses in human tumors were applied to mechanistic analysis of one such overlapping site at chromosome 12p12.1. This defined a novel stage-specific mechanism in which the risk polymorphism, rs12814794, directly creates a new HIF-binding site that mediates HIF-1? isoform specific upregulation of its target BHLHE41. The alignment of multiple sites in the HIF cis-acting apparatus with RCC-susceptibility polymorphisms strongly supports a causal model in which minor variation in this pathway exerts significant effects on RCC development.

Authors with CRIS profile

Victoria Lauer Department of Medicine 4 – Nephrology and Hypertension Franziska Kranz Chair of Visual Computing Margarete Goppelt-Strübe Department of Medicine 4 – Nephrology and Hypertension

Involved external institutions

University of Oxford GB United Kingdom (GB) King Abdulaziz University (KAU) / جامعة الملك عبد العزيز SA Saudi Arabia (SA)

How to cite

APA:

Grampp, S., Schmid, V., Salama, R., Lauer, V., Kranz, F., Platt, J.L.,... Schoedel, J. (2017). Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway. PLoS Genetics, 13, e1006872. https://dx.doi.org/10.1371/journal.pgen.1006872

MLA:

Grampp, Steffen, et al. "Multiple renal cancer susceptibility polymorphisms modulate the HIF pathway." PLoS Genetics 13 (2017): e1006872.

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