The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer
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Large-scale human genetic data1,2,3 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)4,5,6. VHL loss, which is observed in about 90% of ccRCCs, can lead to hypoxia-inducible factor 2α (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 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.
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 . https://doi.org/10.1038/s41586-022-04809-8
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DescriptionG.D.S. is supported by the Mark Foundation for Cancer Research. G.D.S. and A.Y.W. are supported by the Cancer Research UK Cambridge Centre (C9685/A25177). J.S.C. acknowledges support from the University of Cambridge, Cancer Research UK core funding (grants A20411, A31344, A29580 and DRCPGM\100088) and Hutchison Whampoa Ltd. G.D.S., A.Y.W., J.S.C., and the Human Research Tissue Bank were supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The GWAS analysis by M.J.M., M.P.P. and S.J.C. was supported by the Intramural Research Program of the National Cancer Institute, part of the National Institutes of Health. Renal Cancer Research Fund supported TMA studies (D.J.H.). S.H. received a PhD studentship from the Rosetrees Trust. This work was supported by the Medical Research Council (MC_UU_12022/7 and MC_UU_12022/10) and Kidney Research UK (RP_033_20170303).
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