Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors Journal Article


Authors: 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.; Blecua, P.; Cohen-Gould, L.; Jungbluth, A. A.; Rakha, E. A.; Ellis, I. O.; Edelweiss, M. I. A.; Palazzo, J.; Norton, L.; Hollmann, T.; Edelweiss, M.; Rubin, B. P.; Weigelt, B.; Reis-Filho, J. S.
Article Title: Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors
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. © 2018, The Author(s).
Journal Title: Nature Communications
Volume: 9
ISSN: 2041-1723
Publisher: Nature Publishing Group  
Date Published: 2018-08-30
Start Page: 3533
Language: English
DOI: 10.1038/s41467-018-05886-y
PROVIDER: scopus
PMCID: PMC6117336
PUBMED: 30166553
DOI/URL:
Notes: Article -- Export Date: 1 October 2018 -- Source: Scopus
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