Fresia Pareja
Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors
Pareja, Fresia; Brandes, Alissa H.; Basili, Thais; Selenica, Pier; Geyer, Felipe C.; Fan, Dan; Da Cruz Paula, Arnaud; Kumar, Rahul; Brown, David N.; Gularte-Mérida, Rodrigo; Alemar, Barbara; Bi, Rui; Lim, Raymond S.; de Bruijn, Ino; Fujisawa, Sho; Gardner, Rui; Feng, Elvin; Li, Anqi; da Silva, Edaise M.; Lozada, John R.; Blecua, Pedro; Cohen-Gould, Leona; Jungbluth, Achim A.; Rakha, Emad A.; Ellis, Ian O.; Edelweiss, Maria I. A.; Palazzo, Juan; Norton, Larry; Hollmann, Travis; Edelweiss, Marcia; Rubin, Brian P.; Weigelt, Britta; Reis-Filho, Jorge S.
Authors
Alissa H. Brandes
Thais Basili
Pier Selenica
Felipe C. Geyer
Dan Fan
Arnaud Da Cruz Paula
Rahul Kumar
David N. Brown
Rodrigo Gularte-Mérida
Barbara Alemar
Rui Bi
Raymond S. Lim
Ino de Bruijn
Sho Fujisawa
Rui Gardner
Elvin Feng
Anqi Li
Edaise M. da Silva
John R. Lozada
Pedro Blecua
Leona Cohen-Gould
Achim A. Jungbluth
EMAD RAKHA Emad.Rakha@nottingham.ac.uk
Professor of Breast Cancer Pathology
Professor IAN ELLIS IAN.ELLIS@NOTTINGHAM.AC.UK
Professor of Cancer Pathology
Maria I. A. Edelweiss
Juan Palazzo
Larry Norton
Travis Hollmann
Marcia Edelweiss
Brian P. Rubin
Britta Weigelt
Jorge S. Reis-Filho
Abstract
Granular cell tumors (GCTs) are rare tumors that can arise in multiple anatomical locations, and are characterized by abundant intracytoplasmic granules. The genetic drivers of GCTs are currently unknown. Here, we apply whole-exome sequencing and targeted sequencing analysis to reveal mutually exclusive, clonal, inactivating somatic mutations in the endosomal pH regulators ATP6AP1 or ATP6AP2 in 72% of GCTs. Silencing of these genes in vitro results in impaired vesicle acidification, redistribution of endosomal compartments, and accumulation of intracytoplasmic granules, recapitulating the cardinal phenotypic characteristics of GCTs and providing a novel genotypic–phenotypic correlation. In addition, depletion of ATP6AP1 or ATP6AP2 results in the acquisition of oncogenic properties. Our results demonstrate that inactivating mutations of ATP6AP1 and ATP6AP2 are likely oncogenic drivers of GCTs and underpin the genesis of the intracytoplasmic granules that characterize them, providing a genetic link between endosomal pH regulation and tumorigenesis.
Citation
Pareja, F., Brandes, A. H., Basili, T., Selenica, P., Geyer, F. C., Fan, D., …Reis-Filho, J. S. (2018). Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors. Nature Communications, 9, Article 3533. https://doi.org/10.1038/s41467-018-05886-y
Journal Article Type | Article |
---|---|
Acceptance Date | Aug 2, 2018 |
Online Publication Date | Aug 30, 2018 |
Publication Date | Aug 30, 2018 |
Deposit Date | Sep 4, 2018 |
Publicly Available Date | Sep 4, 2018 |
Journal | Nature Communications |
Electronic ISSN | 2041-1723 |
Publisher | Nature Publishing Group |
Peer Reviewed | Peer Reviewed |
Volume | 9 |
Article Number | 3533 |
DOI | https://doi.org/10.1038/s41467-018-05886-y |
Keywords | General Biochemistry, Genetics and Molecular Biology; General Physics and Astronomy; General Chemistry |
Public URL | https://nottingham-repository.worktribe.com/output/1058634 |
Publisher URL | https://www.nature.com/articles/s41467-018-05886-y |
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Publisher Licence URL
https://creativecommons.org/licenses/by/4.0/
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