Targetable NOTCH1 rearrangements in reninoma

被引：3

作者：

Treger, Taryn D. ^{[1
,2
,3
]}

Lawrence, John E. G. ^{[1
,3
]}

Anderson, Nathaniel D. ^{[1
]}

Coorens, Tim H. H. ^{[4
]}

Letunovska, Aleksandra ^{[5
,6
]}

Abby, Emilie ^{[1
]}

Lee-Six, Henry ^{[1
,7
]}

Oliver, Thomas R. W. ^{[1
,7
]}

Al-Saadi, Reem ^{[5
,6
]}

Tullus, Kjell ^{[5
,6
]}

Morcrette, Guillaume ^{[5
,6
]}

Hutchinson, J. Ciaran ^{[6
]}

Rampling, Dyanne ^{[6
]}

Sebire, Neil ^{[5
,6
]}

Pritchard-Jones, Kathy ^{[5
]}

Young, Matthew D. ^{[1
]}

Mitchell, Thomas J. ^{[1
,3
,8
]}

Jones, Philip H. ^{[1
,9
]}

Tran, Maxine ^{[10
,11
]}

Behjati, Sam ^{[1
,2
,3
]}

Chowdhury, Tanzina ^{[5
,6
]}

机构：

[1] Wellcome Sanger Inst, Hinxton CB10 1SA, England

[2] Univ Cambridge, Dept Paediat, Cambridge CB2 0QQ, England

[3] Cambridge Univ Hosp NHS Fdn Trust, Cambridge CB2 0QQ, England

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] UCL Great Ormond St Inst Child Hlth, London WC1N 1EH, England

[6] NIHR Great Ormond St Hosp Biomed Res Ctr, London WC1N 3JH, England

[7] Cambridge Univ Hosp NHS Fdn Trust, Dept Pathol, Cambridge CB2 0QQ, England

[8] Univ Cambridge, Early Canc Inst, Cambridge CB2 0XZ, England

[9] Univ Cambridge, Dept Oncol, Cambridge CB2 OXZ, England

[10] Royal Free Hosp, Specialist Ctr Kidney Canc, London NW3 2QG, England

[11] UCL, Fac Med Sci, Div Surg & Intervent Sci, London NW3 2PS, England

来源：

NATURE COMMUNICATIONS | 2023年 / 14卷 / 01期

基金：

英国惠康基金;

关键词：

CELL; ACTIVATION; MUTATIONS; NUMBER;

D O I：

10.1038/s41467-023-41118-8

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：10

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