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

机译：颗粒细胞瘤中ATP6AP1和ATP6AP2的功能丧失突变

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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.

机译：颗粒细胞瘤（GCT）是一种罕见的肿瘤，可出现在多个解剖部位，其特征是胞浆内颗粒丰富。目前尚不清楚GCT的遗传驱动力。在这里，我们应用全外显子组测序和靶向测序分析来揭示72％的GCT中内体pH调节剂ATP6AP1或ATP6AP2相互排斥，克隆，失活的体细胞突变。这些基因的体外沉默导致囊泡酸化受损，内体区室的重新分布以及胞浆内颗粒的积累，概括了GCT的主要表型特征，并提供了新的基因型-表型相关性。此外，ATP6AP1或ATP6AP2的耗尽导致获得致癌特性。我们的结果表明，ATP6AP1和ATP6AP2的失活突变可能是GCT的致癌驱动因素，并支撑了表征它们的胞浆内颗粒的发生，从而为内体pH调节与肿瘤发生之间提供了遗传联系。

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期刊名称 Nature Communications
作者
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 de 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; Jorge S. Reis-Filho;
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年(卷),期 -1(9),-1
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页码 3533
总页数 13
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1. Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors [J] . Fresia Pareja, Alissa H. Brandes, Thais Basili, Nature Communications . 2018,第1期

机译：颗粒细胞瘤中ATP6AP1和ATP6AP2的功能丧失突变
2. Frequent mutations of genes encoding vacuolar H + + ‐ATPase components in granular cell tumors [J] . Sekimizu Masaya, Yoshida Akihiko, Mitani Sachiyo, Genes, Chromosomes and Cancer . 2019,第6期

机译：在粒状细胞肿瘤中编码真空H ++ -ATP酶组分的基因频繁突变
3. SDHA Loss-of-Function Mutations in KIT–PDGFRA Wild-Type Gastrointestinal Stromal Tumors Identified by Massively Parallel Sequencing [J] . Guido Biasco JNCI: Journal of the National Cancer Institute . 2011,第12期

机译：大规模平行测序鉴定的KIT–PDGFRA野生型胃肠道间质瘤中的SDHA功能丧失突变。
4. Mutational Analysis from Circulating Tumor Cells Using Next-Generation Sequencing [C] . Michael Schwartz, Christine Fu, Tony Tran, International Molecular Medicine Tri-Conference. . 2015

机译：利用下一代测序从循环肿瘤细胞的突变分析
5. NRAS and BRAF mutations in primary cutaneous melanoma: A comparison of mutation rates between radial and vertical growth phases in individual tumors. [D] . Greene, Victoria R. 2007

机译：原发性皮肤黑素瘤中的NRAS和BRAF突变：单个肿瘤在径向和垂直生长期之间的突变率比较。
6. S-100 Negative Granular Cell Tumor (So-called Primitive Polypoid Non-neural Granular Cell Tumor) of the Oral Cavity [O] . Yeshwant B. Rawal, Thomas B. Dodson 2017

机译：口腔的S-100阴性颗粒细胞瘤（所谓的原始息肉样非神经颗粒细胞瘤）
7. SDHA Loss-of-Function Mutations in KIT-PDGFRA Wild-Type Gastrointestinal Stromal Tumors Identified by Massively Parallel Sequencing [O] . M. A. Pantaleo, A. Astolfi, V. Indio, 2011

机译：通过大规模平行测序鉴定的KIT-PDGFRA野生型胃肠道基质肿瘤中的SDHA失去功能突变

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

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