Investigação das alterações genéticas dos ependimomas e gliomas da infância e adolescência utilizando a estratégia de sequenciamento de nova geração

• Ano de defesa: 2021
• Autor(a) principal: Corrêa, Débora Cabral de Carvalho [UNIFESP]
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• dARK ID: ark:/48912/001300001rzss
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo
• Palavras-chave em Português: Tumores de sistema nervoso central; Ependimoma; Gliomas; Sequenciamento de nova geração; Neoplasias da infância e adolescência
• Link de acesso: https://repositorio.unifesp.br/handle/11600/61325

Background: Central nervous system (CNS) tumors represent the most common solid malignancy of childhood and adolescence. Among them, neuroepithelial tumors are the most frequent, comprised mostly by ependymoma (EPN) and gliomas. A specific genetic panel, based on next-generation sequencing (NGS) and developed exclusively for the main pediatric and adolescent neoplasms, is essential for tumor molecular classification into clinically relevant subgroups. Objectives: We aimed to investigate molecular alterations with a potential prognostic marker and therapeutic target in EPNs and gliomas of childhood and adolescence using the NGS strategy. Methods: In order to investigate the presence of somatic genetic variants, we selected 156 CNS tumor samples from patients diagnosed and treated at IOP-GRAACC/UNIFESP, which included 61 EPN samples: 42 posterior fossa (PF-EPN), 14 supratentorial (ST-EPN) and five spinal (SP-EP), and 95 gliomas samples: 56 high-grade gliomas (HGGs) and 39 low-grade gliomas (LGGs). Among the 56 HGGs samples, four were classified as congenital glioblastoma (cGBM). All tumor samples were subjected to targeted sequencing using the Oncomine Childhood Cancer Research Assay® (OCCRA®) panel, specific for the investigation of the most frequent genetic events observed in childhood and adolescence neoplasms. Results: Genetic variants were identified in 24 of 61 (39.3%) EPN samples and in 76 of 95 (80.0%) of gliomas samples. In EPN, the most commonly detected variants were in CIC, ASXL1, and JAK2 genes. In LGGs, the most recurrent alterations were KIAA1549-BRAF fusions and variants in BRAF gene, whereas in HGGs, variants in H3F3A, TP53 and ATRX genes were the most common genetic events. Variants in ALK and NTRK genes were identified in cGBM samples and included alterations distinct from those frequently observed in glioblastoma affecting children and adolescents. Conclusion: Molecular profiling of EPNs and gliomas of childhood and adolescence, using the OCCRA® panel, showed mutational characteristics not yet described in these tumors analyzed by NGS previously. Thus, our findings highlight the clinical importance in identifying new genetic variants for patients’ prognosis and therapeutic orientation.