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.

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., Da Cruz Paula, A., Kumar, R., Brown, D. N., Gularte-Mérida, R., Alemar, B., Bi, R., Lim, R. S., de Bruijn, I., Fujisawa, S., Gardner, R., Feng, E., Li, A., da Silva, E. M., Lozada, J. R., …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
• Contract Date: Sep 4, 2018