Targetable NOTCH1 rearrangements in reninoma

• Published in: Nature communications Vol. 14; no. 1; p. 5826
• Main Authors: Treger, Taryn D., Lawrence, John E. G., Anderson, Nathaniel D., Coorens, Tim H. H., Letunovska, Aleksandra, Abby, Emilie, Lee-Six, Henry, Oliver, Thomas R. W., Al-Saadi, Reem, Tullus, Kjell, Morcrette, Guillaume, Hutchinson, J. Ciaran, Rampling, Dyanne, Sebire, Neil, Pritchard-Jones, Kathy, Young, Matthew D., Mitchell, Thomas J., Jones, Philip H., Tran, Maxine, Behjati, Sam, Chowdhury, Tanzina
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 25-09-2023; Nature Publishing Group; Nature Portfolio
• Subjects: 38/1; 38/23; 38/91; 45/23; 45/91; 631/208/212/2019; 631/208/212/2301; 631/208/69; 631/208/726/649/2157; 631/67/589/1588; 82/1; Blood pressure; Gene sequencing; Genomes; Humanities and Social Sciences; Humans; Juxtaglomerular Apparatus - metabolism; Juxtaglomerular Apparatus - pathology; Kidney Glomerulus - pathology; Kidney Neoplasms - metabolism; Kidneys; multidisciplinary; Notch1 protein; Receptor, Notch1 - genetics; Renin; Renin - metabolism; Science; Science (multidisciplinary); Signal transduction; Signal Transduction - genetics; Smooth muscle; Transcriptomes; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-023-41118-8

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.
Reninomas are very rare kidney tumours of juxtaglomerular cells. Here, the authors analyse reninomas using whole-genome and transcriptome sequencing, and reveal the presence and functional effects of
NOTCH1
rearrangements.