Whole-exome sequencing reveals novel vacuolar ATPase genes' variants and variants in genes involved in lysosomal biology and autophagosomal formation in oral granular cell tumors.
V-ATPase
genetics
lysosomes
oral granular cell tumor
soft tissue neoplasms
Journal
Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology
ISSN: 1600-0714
Titre abrégé: J Oral Pathol Med
Pays: Denmark
ID NLM: 8911934
Informations de publication
Date de publication:
Apr 2021
Apr 2021
Historique:
received:
25
11
2020
accepted:
27
11
2020
pubmed:
9
12
2020
medline:
20
4
2021
entrez:
8
12
2020
Statut:
ppublish
Résumé
Granular cell tumors (GCTs) are rare neuroectodermal soft tissue neoplasms that mainly affect the skin of the upper limbs and trunks and the oral cavity. GCTs are derived from Schwann cells and, ultrastructurally, their intracytoplasmic granules are considered autophagosomes or autophagolysosomes and are consistent with myelin accumulation. In this study, a convenience set of 22 formalin-fixed, paraffin-embedded samples of oral GCTs, all but one sample located at the tongue, was screened for mutations by whole-exome (WES) or targeted sequencing. WES revealed two novel variants in genes of the vacuolar ATPase (V-ATPase) complex: ATP6AP1 frameshift c.746_749del, leading to p.P249Hfs*4, and ATP6V1A non-synonymous c.G868A, leading to p.D290N. Each of these mutations occurred in one case. With regard to the samples that were wild type for these V-ATPase variants, at least two samples presented variants in genes that are part of endosomal/lysosomal/autophagosomal networks including ABCA8, ABCC6, AGAP3, ATG9A, CTSB, DNAJC13, GALC, NPC1, SLC15A3, SLC31A2, and TMEM104. Although the mechanisms involved in oral GCT initiation and progression remain unclear, our results suggest that oral GCTs have V-ATPase variants similarly to GCTs from other tissues/organs, and additionally show variants in lysosomes/endosomes/autophagosomal genes.
Sections du résumé
BACKGROUND
BACKGROUND
Granular cell tumors (GCTs) are rare neuroectodermal soft tissue neoplasms that mainly affect the skin of the upper limbs and trunks and the oral cavity. GCTs are derived from Schwann cells and, ultrastructurally, their intracytoplasmic granules are considered autophagosomes or autophagolysosomes and are consistent with myelin accumulation.
METHODS
METHODS
In this study, a convenience set of 22 formalin-fixed, paraffin-embedded samples of oral GCTs, all but one sample located at the tongue, was screened for mutations by whole-exome (WES) or targeted sequencing.
RESULTS
RESULTS
WES revealed two novel variants in genes of the vacuolar ATPase (V-ATPase) complex: ATP6AP1 frameshift c.746_749del, leading to p.P249Hfs*4, and ATP6V1A non-synonymous c.G868A, leading to p.D290N. Each of these mutations occurred in one case. With regard to the samples that were wild type for these V-ATPase variants, at least two samples presented variants in genes that are part of endosomal/lysosomal/autophagosomal networks including ABCA8, ABCC6, AGAP3, ATG9A, CTSB, DNAJC13, GALC, NPC1, SLC15A3, SLC31A2, and TMEM104.
CONCLUSION
CONCLUSIONS
Although the mechanisms involved in oral GCT initiation and progression remain unclear, our results suggest that oral GCTs have V-ATPase variants similarly to GCTs from other tissues/organs, and additionally show variants in lysosomes/endosomes/autophagosomal genes.
Substances chimiques
ATP6AP1 protein, human
0
Vacuolar Proton-Translocating ATPases
EC 3.6.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
410-417Subventions
Organisme : National Council for Scientific and Technological Development
Informations de copyright
© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
Références
Buley ID, Gatter KC, Kelly PMA, Heryet A, Millard PR. Granular cell tumours revisited. An immunohistological and ultrastructural study. Histopathology. 1988;12(3):263-274.
Machado I, Cruz J, Lavernia J, Llombart-Bosch A. Solitary, multiple, benign, atypical, or malignant: the “Granular Cell Tumor” puzzle. Virchows Arch. 2016;468(5):527-538.
Ordóñez NG, Mackay B. Granular cell tumor: a review of the pathology and histogenesis. Ultrastruct Pathol. 1999;23(4):207-222.
Kurtin PJ, Bonin DM. Immunohistochemical demonstration of the lysosome-associated glycoprotein CD68 (KP-1) in granular cell tumors and schwannomas. Hum Pathol. 1994;25(11):1172-1178.
Mittal KR, True LD. Origin of granules in granular cell tumor. Intracellular myelin formation with autodigestion. Arch Pathol Lab Med. 1988;112(3):302-303.
Bedetti CD, Martinez AJ, Beckford NS, May M. Granular cell tumor arising in myelinated peripheral nerves. Light and electron microscopy and immunoperoxidase study. Virchows Arch A Pathol Anat Histopathol. 1983;402(2):175-183.
Shintaku M. Immunohistochemical localization of autophagosomal membrane-associated protein LC3 in granular cell tumor and schwannoma. Virchows Arch. 2011;459(3):315-319.
Schrader KA, Nelson TN, De Luca A, Huntsman DG, McGillivray BC. Multiple granular cell tumors are an associated feature of LEOPARD syndrome caused by mutation in PTPN11. Clin Genet. 2009;75(2):185-189.
Marchese C, Montera M, Torrini M, et al. Granular cell tumor in a PHTS patient with a novel germline PTEN mutation. Am J Med Genet. 2003;120A(2):286-288.
França JA, de Sousa SF, Moreira RG, et al. Sporadic granular cell tumours lack recurrent mutations in PTPN11, PTEN and other cancer-related genes. J Clin Pathol. 2018;71(1):93-94.
Pareja F, Brandes AH, Basili T, et al. Loss-of-function mutations in ATP6AP1 and ATP6AP2 in granular cell tumors. Nat Commun. 2018;9(1):3533.
Sekimizu M, Yoshida A, Mitani S, et al. Frequent mutations of genes encoding vacuolar H+ -ATPase components in granular cell tumors. Genes Chromosomes Cancer. 2019;58(6):373-380.
Li H, Durbin R. Fast and accurate short read alignment with Burrows-Wheeler transform. Bioinformatics. 2009;25(14):1754-1760.
Li H, Handsaker B, Wysoker A, et al. The sequence alignment/map format and SAMtools. Bioinformatics. 2009;25(16):2078-2079.
Garrison E, Marth G. Haplotype-based variant detection from short-read sequencing. arXiv:1207.3907v2 [q-bio.GN]. July 20. 2012. Available at: https://arxiv.org/abs/1207.3907v2. Accessed April 6, 2020.
McKenna A, Hanna M, Banks E, et al. The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing data. Genome Res. 2010;20(9):1297-1303.
Wang K, Li M, Hakonarson H. ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data. Nucleic Acids Res. 2010;38(16):e164.
Genomes Project C, Abecasis GR, Altshuler D, et al. A map of human genome variation from population-scale sequencing. Nature. 2010;467(7319):1061-1073.
Mitchell AL, Attwood TK, Babbitt PC, et al. InterPro in 2019: improving coverage, classification and access to protein sequence annotations. Nucleic Acids Res. 2019;47(D1):D351-D360.
Schwede T, Kopp J, Guex N, Peitsch MC. SWISS-MODEL: an automated protein homology-modeling server. Nucleic Acids Res. 2003;31(13):3381-3385.
Gomes CC, Fonseca-Silva T, Gomez RS. Evidence for loss of heterozygosity (LOH) at chromosomes 9p and 17p in oral granular cell tumors: a pilot study. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;115(2):249-253.
Forgac M. Vacuolar ATPases: rotary proton pumps in physiology and pathophysiology. Nat Rev Mol Cell Biol. 2007;8(11):917-929.
Wei L, Liu S, Conroy J, et al. Whole-genome sequencing of a malignant granular cell tumor with metabolic response to pazopanib. Cold Spring Harb Mol case Stud. 2015;1(1):a000380.
Schröder BA, Wrocklage C, Hasilik A, Saftig P. The proteome of lysosomes. Proteomics. 2010;10(22):4053-4076.
Chapel A, Kieffer-Jaquinod S, Sagné C, et al. An extended proteome map of the lysosomal membrane reveals novel potential transporters. Mol Cell Proteomics. 2013;12(6):1572-1588.
Sztul E, Chen P-W, Casanova JE, et al. ARF GTPases and their GEFs and GAPs: concepts and challenges. Mol Biol Cell. 2019;30(11):1249-1271.
Bissa B, Beedle A, Govindarajan R. Lysosomal solute carrier transporters gain momentum in research. Clin Pharmacol Ther. 2016;100(5):431-436.
Mizushima N, Yoshimori T, Ohsumi Y. The role of Atg proteins in autophagosome formation. Annu Rev Cell Dev Biol. 2011;27(1):107-132.
Wang C, Zhao T, Li Y, Huang G, White MA, Gao J. Investigation of endosome and lysosome biology by ultra pH-sensitive nanoprobes. Adv Drug Deliv Rev. 2017;113:87-96.
Gomez-Sanchez JA, Carty L, Iruarrizaga-Lejarreta M, et al. Schwann cell autophagy, myelinophagy, initiates myelin clearance from injured nerves. J Cell Biol. 2015;210(1):153-168.