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

Fresia Pareja, Alissa H. Brandes, Thais Basili, Pier Selenica, Felipe C. Geyer, Dan Fan, Arnaud Da Cruz Paula, Rahul Kumar, David N. Brown, Rodrigo Gularte-Mérida, Barbara Alemar, Rui Bi, Raymond S. Lim, Ino Bruijn, Sho Fujisawa, Rui Gardner, Elvin Feng, Anqi Li, Edaise M. da Silva, John R. Lozada, Pedro Blecua, Leona Cohen-Gould, Achim A. Jungbluth, Emad A. Rakha, Ian O. Ellis, Maria I. A. Edelweiss, Juan Palazzo, Larry Norton, Travis Hollmann, Marcia Edelweiss, Brian P. Rubin, Britta Weigelt () and Jorge S. Reis-Filho ()
Additional contact information
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
Rui Bi: Memorial Sloan Kettering Cancer Center
Raymond S. Lim: Memorial Sloan Kettering Cancer Center
Ino 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 Sul
Juan Palazzo: Jefferson Medical College
Larry Norton: Memorial Sloan Kettering Cancer Center
Travis Hollmann: Memorial Sloan Kettering Cancer Center
Marcia Edelweiss: Memorial Sloan Kettering Cancer Center
Brian P. Rubin: Cleveland Clinic
Britta Weigelt: Memorial Sloan Kettering Cancer Center
Jorge S. Reis-Filho: Memorial Sloan Kettering Cancer Center

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05886-y

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