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The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer

Author

Listed:
  • Saroor A. Patel

    (University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus
    Wellcome Sanger Institute)

  • 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
    National Cancer Centre Singapore)

  • 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
    Universiti Kebangsaan Malaysia, Jalan Yaacob Latiff)

  • 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
    University of Helsinki)

  • 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
    Cambridge University Hospitals NHS Foundation Trust)

  • 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
    University of Helsinki
    University of Helsinki)

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.

Suggested Citation

  • 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 & , 2022. "The renal lineage factor PAX8 controls oncogenic signalling in kidney cancer," Nature, Nature, vol. 606(7916), pages 999-1006, June.
    • Handle: RePEc:nat:nature:v:606:y:2022:i:7916:d:10.1038_s41586-022-04809-8
    DOI: 10.1038/s41586-022-04809-8
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