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dc.contributor.authorPatel, Saroor A
dc.contributor.authorHirosue, Shoko
dc.contributor.authorRodrigues, Paulo
dc.contributor.authorVojtasova, Erika
dc.contributor.authorRichardson, Emma K
dc.contributor.authorGe, Jianfeng
dc.contributor.authorSyafruddin, Saiful E
dc.contributor.authorSpeed, Alyson
dc.contributor.authorPapachristou, Evangelia K
dc.contributor.authorBaker, David
dc.contributor.authorClarke, David
dc.contributor.authorPurvis, Stephenie
dc.contributor.authorWesolowski, Ludovic
dc.contributor.authorDyas, Anna
dc.contributor.authorCastillon, Leticia
dc.contributor.authorCaraffini, Veronica
dc.contributor.authorBihary, Dóra
dc.contributor.authorYong, Cissy
dc.contributor.authorHarrison, David J
dc.contributor.authorStewart, Grant D
dc.contributor.authorMachiela, Mitchell J
dc.contributor.authorPurdue, Mark P
dc.contributor.authorChanock, Stephen J
dc.contributor.authorWarren, Anne Y
dc.contributor.authorSamarajiwa, Shamith A
dc.contributor.authorCarroll, Jason S
dc.contributor.authorVanharanta, Sakari
dc.date.accessioned2022-06-23T10:30:02Z
dc.date.available2022-06-23T10:30:02Z
dc.date.issued2022-06-30
dc.identifier.citationPatel , 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/s41586-022-04809-8en
dc.identifier.issn0028-0836
dc.identifier.otherPURE: 279307601
dc.identifier.otherPURE UUID: 83d8930d-20e8-4886-ace1-29fcb8e106ed
dc.identifier.otherJisc: 403554
dc.identifier.otherPubMed: 35676472
dc.identifier.otherpii: 10.1038/s41586-022-04809-8
dc.identifier.otherScopus: 85131551240
dc.identifier.otherORCID: /0000-0001-9041-9988/work/114977238
dc.identifier.urihttp://hdl.handle.net/10023/25558
dc.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).en
dc.description.abstractLarge-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.
dc.format.extent35
dc.language.isoeng
dc.relation.ispartofNatureen
dc.rightsCopyright © The Author(s) 2022. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.en
dc.subjectRC0254 Neoplasms. Tumors. Oncology (including Cancer)en
dc.subjectQH426 Geneticsen
dc.subjectDASen
dc.subject.lccRC0254en
dc.subject.lccQH426en
dc.titleThe renal lineage factor PAX8 controls oncogenic signalling in kidney canceren
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. School of Medicineen
dc.contributor.institutionUniversity of St Andrews. Sir James Mackenzie Institute for Early Diagnosisen
dc.contributor.institutionUniversity of St Andrews. Cellular Medicine Divisionen
dc.identifier.doihttps://doi.org/10.1038/s41586-022-04809-8
dc.description.statusPeer revieweden


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