Targetable NOTCH1 Rearrangements in Reninoma

Overview

Journal Nat Commun

Specialty Biology

Date 2023 Sep 25

PMID 37749094

Authors

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

Affiliations

Soon will be listed here.

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.

Citing Articles

Hallmark discoveries in the biology of non-Wilms tumour childhood kidney cancers.

Perotti D, OSullivan M, Walz A, Davick J, Al-Saadi R, Benedetti D Nat Rev Urol. 2025; .

PMID: 39881003 DOI: 10.1038/s41585-024-00993-6.

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