Document Type
Article
Publication Date
12-1-2018
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.
Recommended Citation
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 P.; Norton, Larry; Hollmann, Travis; Edelweiss, Marcia; Rubin, Brian P.; Weigelt, Britta; and Reis-Filho, Jorge S., "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors." (2018). Department of Pathology, Anatomy, and Cell Biology Faculty Papers. Paper 241.
https://jdc.jefferson.edu/pacbfp/241
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 License.
PubMed ID
30166553
Language
English
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.