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Targetable NOTCH1 rearrangements in reninoma

Author

Listed:
  • Taryn D. Treger

    (Wellcome Sanger Institute
    University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • John E. G. Lawrence

    (Wellcome Sanger Institute
    Cambridge University Hospitals NHS Foundation Trust)

  • Nathaniel D. Anderson

    (Wellcome Sanger Institute)

  • Tim H. H. Coorens

    (Broad Institute of MIT and Harvard)

  • Aleksandra Letunovska

    (UCL Great Ormond Street Institute of Child Health
    NIHR Great Ormond Street Hospital Biomedical Research Centre)

  • Emilie Abby

    (Wellcome Sanger Institute)

  • Henry Lee-Six

    (Wellcome Sanger Institute
    Cambridge University Hospitals NHS Foundation Trust)

  • Thomas R. W. Oliver

    (Wellcome Sanger Institute
    Cambridge University Hospitals NHS Foundation Trust)

  • Reem Al-Saadi

    (UCL Great Ormond Street Institute of Child Health
    NIHR Great Ormond Street Hospital Biomedical Research Centre)

  • Kjell Tullus

    (UCL Great Ormond Street Institute of Child Health
    NIHR Great Ormond Street Hospital Biomedical Research Centre)

  • Guillaume Morcrette

    (UCL Great Ormond Street Institute of Child Health
    NIHR Great Ormond Street Hospital Biomedical Research Centre)

  • J. Ciaran Hutchinson

    (NIHR Great Ormond Street Hospital Biomedical Research Centre)

  • Dyanne Rampling

    (NIHR Great Ormond Street Hospital Biomedical Research Centre)

  • Neil Sebire

    (UCL Great Ormond Street Institute of Child Health
    NIHR Great Ormond Street Hospital Biomedical Research Centre)

  • Kathy Pritchard-Jones

    (UCL Great Ormond Street Institute of Child Health)

  • Matthew D. Young

    (Wellcome Sanger Institute)

  • Thomas J. Mitchell

    (Wellcome Sanger Institute
    Cambridge University Hospitals NHS Foundation Trust
    University of Cambridge)

  • Philip H. Jones

    (Wellcome Sanger Institute
    University of Cambridge)

  • Maxine Tran

    (Royal Free Hospital
    University College London)

  • Sam Behjati

    (Wellcome Sanger Institute
    University of Cambridge
    Cambridge University Hospitals NHS Foundation Trust)

  • Tanzina Chowdhury

    (UCL Great Ormond Street Institute of Child Health
    NIHR Great Ormond Street Hospital Biomedical Research Centre)

Abstract

Reninomas are exceedingly rare renin-secreting kidney tumours that derive from juxtaglomerular cells, specialised smooth muscle cells that reside at the vascular inlet of glomeruli. They are the central component of the juxtaglomerular apparatus which controls systemic blood pressure through the secretion of renin. We assess somatic changes in reninoma and find structural variants that generate canonical activating rearrangements of, NOTCH1 whilst removing its negative regulator, NRARP. Accordingly, in single reninoma nuclei we observe excessive renin and NOTCH1 signalling mRNAs, with a concomitant non-excess of NRARP expression. Re-analysis of previously published reninoma bulk transcriptomes further corroborates our observation of dysregulated Notch pathway signalling in reninoma. Our findings reveal NOTCH1 rearrangements in reninoma, therapeutically targetable through existing NOTCH1 inhibitors, and indicate that unscheduled Notch signalling may be a disease-defining feature of reninoma.

Suggested Citation

  • Taryn D. Treger & John E. G. Lawrence & Nathaniel D. Anderson & Tim H. H. Coorens & Aleksandra Letunovska & Emilie Abby & Henry Lee-Six & Thomas R. W. Oliver & Reem Al-Saadi & Kjell Tullus & Guillaume, 2023. "Targetable NOTCH1 rearrangements in reninoma," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-41118-8
    DOI: 10.1038/s41467-023-41118-8
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    References listed on IDEAS

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    1. Bing He & Ping Chen & Sonia Zambrano & Dina Dabaghie & Yizhou Hu & Katja Möller-Hackbarth & David Unnersjö-Jess & Gül Gizem Korkut & Emmanuelle Charrin & Marie Jeansson & Maria Bintanel-Morcillo & Ann, 2021. "Single-cell RNA sequencing reveals the mesangial identity and species diversity of glomerular cell transcriptomes," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
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    3. Matthew D. Young & Thomas J. Mitchell & Lars Custers & Thanasis Margaritis & Francisco Morales-Rodriguez & Kwasi Kwakwa & Eleonora Khabirova & Gerda Kildisiute & Thomas R. W. Oliver & Ronald R. Krijge, 2021. "Single cell derived mRNA signals across human kidney tumors," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
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