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The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer.

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.
Authors:
SA Patel, S Hirosue, P Rodrigues, E Vojtasova, EK Richardson, J Ge, SE Syafruddin, A Speed, EK Papachristou, D Baker, D Clarke, S Purvis, L Wesolowski, A Dyas, L Castillon, V Caraffini, D Bihary, C Yong, DJ Harrison, GD Stewart, MJ Machiela, MP Purdue, SJ Chanock, AY Warren, SA Samarajiwa, JS Carroll, S Vanharanta
Journal:
Nature
Citation info:
606(7916):999-1006
Publication date:
1st Jun 2022
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