Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors
Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors
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DOI：
10.1038/s41467-018-05886-y
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发表时间：
2018-08-30
影响因子：
16.6
通讯作者：
Reis-Filho, Jorge S.
中科院分区：
文献类型：
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作者：
Pareja, Fresia;Brandes, Alissa H.;Reis-Filho, Jorge S.
颗粒细胞肿瘤(GCTS)是一种罕见的肿瘤，可发生在多个解剖部位，其特点是胞浆内有丰富的颗粒。GCTS的遗传驱动因素目前尚不清楚。在这里，我们应用全外显子测序和靶向测序分析，揭示了72%的GCTS中内体pH调节因子ATP6AP1或ATP6AP2的相互排斥、克隆性、失活的体细胞突变。在体外沉默这些基因会导致受损的囊泡酸化、内体隔室的重新分布和胞浆内颗粒的聚集，概括了GCTS的主要表型特征，并提供了一种新的基因-表型相关性。此外，ATP6AP1或ATP6AP2的缺失会导致致癌特性的获得。我们的结果表明，ATP6AP1和ATP6AP2的失活突变可能是GCTS的致癌驱动因素，并支持表征它们的胞浆内颗粒的发生，提供了内体pH调节和肿瘤发生之间的遗传联系。
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.