Identificação de Drivers Moleculares no Tumor de Células Granulares Oral

• Ano de defesa: 2020
• Autor(a) principal: Josiane Alves França
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de Minas Gerais; Brasil; MEDICINA - FACULDADE DE MEDICINA; Programa de Pós-Graduação em Medicina Molecular; UFMG
• Palavras-chave em Português: Tumor de células granulares oral; Sequenciamento de nova geração; Sequenciamento completo do exoma; Genética; Mutações; Lisossomos; V-ATPase; Tumor de Células Granulares; Sequenciamento de Nucleotídeos em Larga Escala; Sequenciamento Completo do Exoma; ATPases Vacuolares Próton­-Translocadoras
• Link de acesso: http://hdl.handle.net/1843/36716

Granular cell tumor (GCT) is a benign soft tissue neoplasm of unknown pathogenesis that mainly affects the head and neck region. GCTs are derived from Schwann cells and, utrastructurally, their intracytoplasmic granules are considered autophagosomes or autophagolysosomes, and are consistent with myelin accumulation. In this study, a convenience sample of oral GCTs was sequenced by next generation sequencing in order to investigate the presence of pathogenic variants. In a first step, we investigated the presence of driver mutations in sporadic oral GCT by targeted next-generation sequencing using a panel of 50 oncogenes and tumor suppressor genes commonly altered in human neoplasms. Mutations in KDR, GNAQ and ATM were reported for the first time, but no recurrent mutations were observed in the discovery cohort of 6 tumors. In a second step, we seek to identify driver mutations without using a panel of predefined targets, therefore using the Whole-exome sequencing (WES) technique to sequence a discovery cohort of 7 tumors. WES results showed two new variants in genes of the V-ATPase complex: ATP6AP1 frameshift deletion c.746_749del, leading to p.P249Hfs*4, and ATP6V1A nonsynonymous SNV c.G868A, leading to p.D290N. These variants occurred in one case each and were investigated by Sanger sequencing in 15 more samples, not being detected in any of them. With regard to the 5 samples that were wild-type for for the variants in genes of V-ATPase complex, 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 remains 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.