Targetable NOTCH1 rearrangements in reninoma.
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Peer-reviewed
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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.
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Acknowledgements: This project was funded by The Little Princess Trust (grant number CCLGA 2019 27) and the Wellcome Trust Grants (grants 206194; 108413/A/15/D; 223135/Z/21/Z). G.M. was supported by La Ligue Contre le Cancer and by Assistance Publique Hôpitaux de Paris. P.J. is supported by a grant from the Wellcome Trust to the Wellcome Sanger Institute, 296194 and a Cancer Research UK Programme Grant, C609/A27326. We thank Professor Freddy Ratke for sharing his expertise on NOTCH1 and Professor Jan Danser for helping us access raw sequencing data of his reninoma study. We thank the clinical teams involved in the care of patients, in particular Professor Imran Mushtaq, Mrs Eileen Brennan and Dr Lauren Roe of Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK. We are indebted to our patients and their families for participating in this research.
Funder: The Little Princess Trust (grant number CCLGA 2019 27) and the Wellcome Trust Grants (grants 206194; 108413/A/15/D; 223135/Z/21/Z).
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2041-1723
