Renal lineage factor PAX8 controls oncogenic signalling in kidney cancer
Authors
Vanharanta, Sakari
Patel, saroor
Carroll, jason
Samarajiwa, Shamith
Yong, cissy
Hirosue, shoko
rodrigues, paulo
Vojtasova, erika
Richardson, emma
Syafruddin, saiful
speed, alyson
Journal Title
Nature
ISSN
0028-0836
Publisher
Nature Research
Type
Article
This Version
AM
Metadata
Show full item recordCitation
Stewart, G., Vanharanta, S., Patel, s., Warren, A., Carroll, j., Samarajiwa, S., Yong, c., et al. Renal lineage factor PAX8 controls oncogenic signalling in kidney cancer. Nature https://doi.org/10.17863/CAM.84021
Abstract
Based on large-scale human genetic data1–3, cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analysis of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common clear cell renal cell carcinoma (ccRCC)-causing genetic alterations in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL)4–6. VHL loss, observed in ~90% of ccRCCs, can lead to hypoxia-inducible factor 2 alpha (HIF2A) stabilization6,7. We show that HIF2A is preferentially recruited to PAX8-bound transcriptional enhancers, including a pro-tumorigenic cyclin D1 (CCND1) enhancer that is controlled by PAX8 and HIF2A. The ccRCC protective allele C at rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports proliferation of normal renal epithelial cells is also required for MYC expression from the ccRCC metastasis-associated amplicons at 8q21.3-q24.3 (ref. 8). These results demonstrate that transcriptional lineage factors are essential for oncogenic signalling and they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants.
Sponsorship
Medical Research Council (MC_UU_12022/7 and MC_UU_12022/10) and Kidney Research UK (RP_033_20170303).
Identifiers
This record's DOI: https://doi.org/10.17863/CAM.84021
This record's URL: https://www.repository.cam.ac.uk/handle/1810/336599
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