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Nat Commun. 2018 Aug 30;9(1):3533. doi: 10.1038/s41467-018-05886-y.

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

Author information

1
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
2
Genetics and Molecular Biology, Federal University of Rio Grande do Sul, Porto Alegre, 91501-970, Brazil.
3
Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
4
Molecular Cytology Core Facility, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
5
Flow Cytometry Core Facility, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
6
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
7
Department of Biochemistry, Weill Cornell Medical College, New York, 10065, NY, USA.
8
Department of Pathology, University of Nottingham, Nottingham, NG7 2RD, UK.
9
Hospital de Clínicas, Federal University of Rio Grande do Sul, Porto Alegre, 90035-903, Brazil.
10
Department of Pathology, Jefferson Medical College, Philadelphia, 19107, PA, USA.
11
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
12
Departments of Pathology and Cancer Biology, Robert J. Tomsich Pathology and Laboratory Medicine Institute and The Lerner Research Institute, Cleveland Clinic, Cleveland, 44195, OH, USA.
13
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA. weigeltb@mskcc.org.
14
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA. reisfilj@mskcc.org.

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.

PMID:
30166553
PMCID:
PMC6117336
DOI:
10.1038/s41467-018-05886-y
[Indexed for MEDLINE]
Free PMC Article

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