Targetable NOTCH1 rearrangements in reninoma

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 Morcrette, J. Ciaran Hutchinson, Dyanne Rampling, Neil Sebire, Kathy Pritchard-Jones, Matthew D. Young, Thomas J. Mitchell, Philip H. Jones, Maxine Tran (), Sam Behjati () and Tanzina Chowdhury ()
Additional contact information
Taryn D. Treger: Wellcome Sanger Institute
John E. G. Lawrence: Wellcome Sanger Institute
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
Emilie Abby: Wellcome Sanger Institute
Henry Lee-Six: Wellcome Sanger Institute
Thomas R. W. Oliver: Wellcome Sanger Institute
Reem Al-Saadi: UCL Great Ormond Street Institute of Child Health
Kjell Tullus: UCL Great Ormond Street Institute of Child Health
Guillaume Morcrette: UCL Great Ormond Street Institute of Child Health
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
Kathy Pritchard-Jones: UCL Great Ormond Street Institute of Child Health
Matthew D. Young: Wellcome Sanger Institute
Thomas J. Mitchell: Wellcome Sanger Institute
Philip H. Jones: Wellcome Sanger Institute
Maxine Tran: Royal Free Hospital
Sam Behjati: Wellcome Sanger Institute
Tanzina Chowdhury: UCL Great Ormond Street Institute of Child Health

Nature Communications, 2023, vol. 14, issue 1, 1-10

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-41118-8

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