Nature Communications (Sep 2023)

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,
  • Tanzina Chowdhury

DOI
https://doi.org/10.1038/s41467-023-41118-8
Journal volume & issue
Vol. 14, no. 1
pp. 1 – 10

Abstract

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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.