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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, Eva
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
dc.contributor.authorMachiela, Mitchell J
dc.contributor.authorPurdue, Mark P
dc.contributor.authorChanock, Stephen J
dc.contributor.authorWarren, Anne
dc.contributor.authorSamarajiwa, Shamith A
dc.contributor.authorCarroll, Jason
dc.contributor.authorVanharanta, Sakari
dc.date.accessioned2022-06-29T19:50:38Z
dc.date.available2022-06-29T19:50:38Z
dc.date.issued2022-06-08
dc.date.submitted2021-02-11
dc.identifier.issn0028-0836
dc.identifier.others41586-022-04809-8
dc.identifier.other4809
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/338610
dc.description.abstractLarge-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.
dc.description.sponsorshipMedical Research Council (MC_UU_12022/7 and MC_UU_12022/10) and Kidney Research UK (RP_033_20170303).
dc.languageen
dc.publisherSpringer Science and Business Media LLC
dc.subjectArticle
dc.subject/631/67/69
dc.subject/631/208/191
dc.subject/631/67/70
dc.subject/631/208/200
dc.subject/692/699/67/589/1588/1351
dc.subject/38/32
dc.subject/38/39
dc.subject/38/35
dc.subject/38/89
dc.subject/38/91
dc.subject/38/109
dc.subject/82/58
dc.subject/13
dc.subject/13/31
dc.subject/13/106
dc.subject/45
dc.subject/45/15
dc.subject/45/41
dc.subject/45/43
dc.subject/64
dc.subject/64/60
dc.subject/59
dc.subject/59/5
dc.subject/42
dc.subject/82/29
dc.subject/82/80
dc.subjectarticle
dc.titleThe renal lineage factor PAX8 controls oncogenic signalling in kidney cancer.
dc.typeArticle
dc.date.updated2022-06-29T19:50:37Z
prism.endingPage1006
prism.issueIdentifier7916
prism.publicationNameNature
prism.startingPage999
prism.volume606
dc.identifier.doi10.17863/CAM.86023
dcterms.dateAccepted2022-04-27
rioxxterms.versionofrecord10.1038/s41586-022-04809-8
rioxxterms.versionVoR
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
dc.contributor.orcidHirosue, Shoko [0000-0003-1287-471X]
dc.contributor.orcidVojtasova, Erika [0000-0001-9255-8551]
dc.contributor.orcidPapachristou, Eva [0000-0002-5835-2055]
dc.contributor.orcidHarrison, David J [0000-0001-9041-9988]
dc.contributor.orcidStewart, Grant [0000-0003-3188-9140]
dc.contributor.orcidMachiela, Mitchell J [0000-0001-6538-9705]
dc.contributor.orcidChanock, Stephen J [0000-0002-2324-3393]
dc.contributor.orcidWarren, Anne [0000-0002-1170-7867]
dc.contributor.orcidSamarajiwa, Shamith A [0000-0003-1046-0601]
dc.contributor.orcidCarroll, Jason [0000-0003-3643-0080]
dc.contributor.orcidVanharanta, Sakari [0000-0001-5619-7963]
dc.identifier.eissn1476-4687
pubs.funder-project-idMedical Research Council (MC_UU_12022/7)
pubs.funder-project-idCancer Research UK (C96/A25177)
pubs.funder-project-idKidney Research UK (RP_033_20170303)
pubs.funder-project-idMRC (MC_UU_12022/10)
pubs.funder-project-idEuropean Commission Horizon 2020 (H2020) Marie Sk?odowska-Curie actions (955951)
pubs.funder-project-idNational Institute for Health Research (NIHRDH-IS-BRC-1215-20014)
cam.issuedOnline2022-06-08


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