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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

Nature communications, 2018-08, Vol.9 (1), p.3533-13, Article 3533 [Periódico revisado por pares]

England: Nature Publishing Group

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Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors
Autor: 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
Assuntos: Acidification ; Cell Proliferation - genetics ; Cell Proliferation - physiology ; Exome ; Female ; Flow Cytometry ; Gene sequencing ; Gene silencing ; Genetic Association Studies ; Granular Cell Tumor - genetics ; Granular materials ; HEK293 Cells ; Humans ; Male ; Mutation ; Mutation - genetics ; pH effects ; Receptors, Cell Surface - genetics ; Regulators ; Tumorigenesis ; Tumors ; Vacuolar Proton-Translocating ATPases - genetics
É parte de: Nature communications, 2018-08, Vol.9 (1), p.3533-13, Article 3533
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SourceType-Scholarly Journals-1
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Descrição: 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.
Editor: England: Nature Publishing Group
Idioma: Inglês

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

England: Nature Publishing Group

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