The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer

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Patel , S A , Hirosue , S , Rodrigues , P , Vojtasova , E , Richardson , E K , Ge , J , Syafruddin , S E , Speed , A , Papachristou , E K , Baker , D , Clarke , D , Purvis , S , Wesolowski , L , Dyas , A , Castillon , L , Caraffini , V , Bihary , D , Yong , C , Harrison , D J , Stewart , G D , Machiela , M J , Purdue , M P , Chanock , S J , Warren , A Y , Samarajiwa , S A , Carroll , J S & Vanharanta , S 2022 , ' The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer ' , Nature , vol. 606 , no. 7916 , pp. 999-+ . https://doi.org/10.1038/s41586-022-04809-8

Title: The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer
Author: Patel, Saroor A.; Hirosue, Shoko; Rodrigues, Paulo; Vojtasova, Erika; Richardson, Emma K.; Ge, Jianfeng; Syafruddin, Saiful E.; Speed, Alyson; Papachristou, Evangelia K.; Baker, David; Clarke, David; Purvis, Stephenie; Wesolowski, Ludovic; Dyas, Anna; Castillon, Leticia; Caraffini, Veronica; Bihary, Dora; Yong, Cissy; Harrison, David J.; Stewart, Grant D.; Machiela, Mitchell J.; Purdue, Mark P.; Chanock, Stephen J.; Warren, Anne Y.; Samarajiwa, Shamith A.; Carroll, Jason S.; Vanharanta, Sakari
Contributor organization: CAN-PRO - Translational Cancer Medicine Program
Department of Physiology
Faculty of Medicine
University of Helsinki
Date: 2022-06-30
Language: eng
Number of pages: 27
Belongs to series: Nature
ISSN: 0028-0836
DOI: https://doi.org/10.1038/s41586-022-04809-8
URI: http://hdl.handle.net/10138/346323
Abstract: Large-scale human genetic data(1-3) have shown that cancer mutations display strong tissue-selectivity, but how this selectivity arises remains unclear. Here, using experimental models, functional genomics and analyses of patient samples, we demonstrate that the lineage transcription factor paired box 8 (PAX8) is required for oncogenic signalling by two common genetic alterations that cause clear cell renal cell carcinoma (ccRCC) in humans: the germline variant rs7948643 at 11q13.3 and somatic inactivation of the von Hippel-Lindau tumour suppressor (VHL)(4-6). VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2 alpha (HIF2A) stabilization(6,7). 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 Cat rs7948643 inhibits PAX8 binding at this enhancer and downstream activation of CCND1 expression. Co-option of a PAX8-dependent physiological programme that supports the 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 that they mediate tissue-specific cancer risk associated with somatic and inherited genetic variants.
Subject: CYCLIN D1
HIF
SUSCEPTIBILITY
BINDING
SPECIFICITY
PROMOTES
ENHANCER
TARGET
GENE
3122 Cancers
Peer reviewed: Yes
Rights: cc_by
Usage restriction: openAccess
Self-archived version: publishedVersion


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