Authors

Fresia Pareja, Memorial Sloan Kettering Cancer Center
Alissa H. Brandes, Memorial Sloan Kettering Cancer Center
Thais Basili, Memorial Sloan Kettering Cancer Center
Pier Selenica, Memorial Sloan Kettering Cancer Center
Felipe C. Geyer, Memorial Sloan Kettering Cancer Center
Dan Fan, Memorial Sloan Kettering Cancer Center
Arnaud Da Cruz Paula, Memorial Sloan Kettering Cancer Center
Rahul Kumar, Memorial Sloan Kettering Cancer Center
David N. Brown, Memorial Sloan Kettering Cancer Center
Rodrigo Gularte-Mérida, Memorial Sloan Kettering Cancer Center
Barbara Alemar, Memorial Sloan Kettering Cancer Center; Federal University of Rio Grande do Sul
Rui Bi, Memorial Sloan Kettering Cancer Center; Fudan University Shanghai Cancer Center
Raymond S. Lim, Memorial Sloan Kettering Cancer Center
Ino de Bruijn, Memorial Sloan Kettering Cancer Center
Sho Fujisawa, Memorial Sloan Kettering Cancer Center
Rui Gardner, Memorial Sloan Kettering Cancer Center
Elvin Feng, Memorial Sloan Kettering Cancer Center
Anqi Li, Memorial Sloan Kettering Cancer Center
Edaise M. da Silva, Memorial Sloan Kettering Cancer Center
John R. Lozada, Memorial Sloan Kettering Cancer Center
Pedro Blecua, Memorial Sloan Kettering Cancer Center
Leona Cohen-Gould, Weill Cornell Medical College
Achim A. Jungbluth, Memorial Sloan Kettering Cancer Center
Emad A. Rakha, University of Nottingham
Ian O. Ellis, University of Nottingham
Maria I.A. Edelweiss, Federal University of Rio Grande do SulFollow
Juan P. Palazzo, Thomas Jefferson UniversityFollow
Larry Norton, Memorial Sloan Kettering Cancer Center
Travis Hollmann, Memorial Sloan Kettering Cancer Center
Marcia Edelweiss, Memorial Sloan Kettering Cancer CenterFollow
Brian P. Rubin, Cleveland Clinic
Britta Weigelt, Memorial Sloan Kettering Cancer CenterFollow
Jorge S. Reis-Filho, Memorial Sloan Kettering Cancer Center

Document Type

Article

Publication Date

12-1-2018

Comments

This article has been peer reviewed. It is the author’s final published version in Nature Communications, Volume 9, Issue 1, December 2018, Article number 3533.

The published version is available at https://doi.org/10.1038/s41467-018-05886-y. Copyright © Pareja et al.

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.

Creative Commons License

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

30166553

Language

English

Available for download on Saturday, December 01, 2018

Included in

Pathology Commons

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