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

Author

Listed:
  • 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
    Federal University of Rio Grande do Sul)

  • Rui Bi

    (Memorial Sloan Kettering Cancer Center
    Fudan University Shanghai 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
    Fudan University Shanghai 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)

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.

Suggested Citation

  • 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 & , 2018. "Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-05886-y
    DOI: 10.1038/s41467-018-05886-y
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    Cited by:

    1. Juan Blanco-Heredia & Carla Anjos Souza & Juan L. Trincado & Maria Gonzalez-Cao & Samuel Gonçalves-Ribeiro & Sara Ruiz Gil & Dmytro Pravdyvets & Samandhy Cedeño & Maurizio Callari & Antonio Marra & An, 2024. "Converging and evolving immuno-genomic routes toward immune escape in breast cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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