The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer

Saroor A. Patel, Shoko Hirosue, Paulo Rodrigues, Erika Vojtasova, Emma K. Richardson, Jianfeng Ge, Saiful E. Syafruddin, Alyson Speed, Evangelia K. Papachristou, David Baker, David Clarke, Stephenie Purvis, Ludovic Wesolowski, Anna Dyas, Leticia Castillon, Veronica Caraffini, Dóra Bihary, Cissy Yong, David J. Harrison, Grant D. Stewart, Mitchell J. Machiela, Mark P. Purdue, Stephen J. Chanock, Anne Y. Warren, Shamith A. Samarajiwa, Jason S. Carroll and Sakari Vanharanta ()
Additional contact information
Saroor A. Patel: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Shoko Hirosue: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Paulo Rodrigues: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Erika Vojtasova: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Emma K. Richardson: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Jianfeng Ge: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Saiful E. Syafruddin: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Alyson Speed: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Evangelia K. Papachristou: University of Cambridge, Robinson Way
David Baker: Norwich Research Park
David Clarke: Cambridge University Hospitals NHS Foundation Trust
Stephenie Purvis: Cambridge University Hospitals NHS Foundation Trust
Ludovic Wesolowski: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Anna Dyas: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Leticia Castillon: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Veronica Caraffini: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Dóra Bihary: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Cissy Yong: University of Cambridge, Cambridge Biomedical Campus
David J. Harrison: University of St Andrews
Grant D. Stewart: University of Cambridge, Cambridge Biomedical Campus
Mitchell J. Machiela: National Cancer Institute
Mark P. Purdue: National Cancer Institute
Stephen J. Chanock: National Cancer Institute
Anne Y. Warren: Cambridge University Hospitals NHS Foundation Trust
Shamith A. Samarajiwa: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
Jason S. Carroll: University of Cambridge, Robinson Way
Sakari Vanharanta: University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus

Nature, 2022, vol. 606, issue 7916, 999-1006

Abstract: Abstract Large-scale human genetic data1–3 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 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.

Date: 2022
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DOI: 10.1038/s41586-022-04809-8

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