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; Sakari Vanharanta

doi:10.1038/s41586-022-04809-8

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 StewartMitchell J Machiela, Mark P Purdue, Stephen J Chanock, Anne Y Warren, Shamith A Samarajiwa, Jason S Carroll, Sakari Vanharanta^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

Abstract

Large-scale human genetic data^1,2,3 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) stabilization^6,7. 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.

Original language	English
Number of pages	35
Journal	Nature
Early online date	8 Jun 2022
DOIs	https://doi.org/10.1038/s41586-022-04809-8
Publication status	Published - 30 Jun 2022

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The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer (dataset)
Harrison, D. J. (Creator), NCBI GenBank, 2022
https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE163001 and 4 more links, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE162948, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE163000, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE163485, https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE163487 (show fewer)
Dataset

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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., ... Vanharanta, S. (2022). The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer. Nature. https://doi.org/10.1038/s41586-022-04809-8

@article{83d8930d20e84886ace129fcb8e106ed,

title = "The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer",

abstract = "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.",

author = "Patel, {Saroor A} and Shoko Hirosue and Paulo Rodrigues and Erika Vojtasova and Richardson, {Emma K} and Jianfeng Ge and Syafruddin, {Saiful E} and Alyson Speed and Papachristou, {Evangelia K} and David Baker and David Clarke and Stephenie Purvis and Ludovic Wesolowski and Anna Dyas and Leticia Castillon and Veronica Caraffini and D{\'o}ra Bihary and Cissy Yong and Harrison, {David J} and Stewart, {Grant D} and Machiela, {Mitchell J} and Purdue, {Mark P} and Chanock, {Stephen J} and Warren, {Anne Y} and Samarajiwa, {Shamith A} and Carroll, {Jason S} and Sakari Vanharanta",

note = "G.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). ",

year = "2022",

month = jun,

day = "30",

doi = "10.1038/s41586-022-04809-8",

language = "English",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature publishing group",

}

Patel, SA, Hirosue, S, Rodrigues, P, Vojtasova, E, Richardson, EK, Ge, J, Syafruddin, SE, Speed, A, Papachristou, EK, Baker, D, Clarke, D, Purvis, S, Wesolowski, L, Dyas, A, Castillon, L, Caraffini, V, Bihary, D, Yong, C, Harrison, DJ, Stewart, GD, Machiela, MJ, Purdue, MP, Chanock, SJ, Warren, AY, Samarajiwa, SA, Carroll, JS & Vanharanta, S 2022, 'The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer', Nature. https://doi.org/10.1038/s41586-022-04809-8

TY - JOUR

T1 - The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer

AU - Patel, Saroor A

AU - Hirosue, Shoko

AU - Rodrigues, Paulo

AU - Vojtasova, Erika

AU - Richardson, Emma K

AU - Ge, Jianfeng

AU - Syafruddin, Saiful E

AU - Speed, Alyson

AU - Papachristou, Evangelia K

AU - Baker, David

AU - Clarke, David

AU - Purvis, Stephenie

AU - Wesolowski, Ludovic

AU - Dyas, Anna

AU - Castillon, Leticia

AU - Caraffini, Veronica

AU - Bihary, Dóra

AU - Yong, Cissy

AU - Harrison, David J

AU - Stewart, Grant D

AU - Machiela, Mitchell J

AU - Purdue, Mark P

AU - Chanock, Stephen J

AU - Warren, Anne Y

AU - Samarajiwa, Shamith A

AU - Carroll, Jason S

AU - Vanharanta, Sakari

N1 - G.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).

PY - 2022/6/30

Y1 - 2022/6/30

N2 - 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.

AB - 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.

U2 - 10.1038/s41586-022-04809-8

DO - 10.1038/s41586-022-04809-8

M3 - Article

C2 - 35676472

SN - 0028-0836

JO - Nature

JF - Nature

ER -

The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer

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The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer (dataset)

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