Expansão da caracterização molecular do ameloblastoma adenoide utilizando sequenciamento de nova geração de um painel de oncogenes e genes supressores de tumor.

Abstract

Adenoid ameloblastoma (AA) is a rare epithelial odontogenic tumor characterized microscopically by ameloblastoma-like epithelium, duct-like structures, moruliform structures, and cribriform architecture, frequently presenting with dentinoid matrix deposition, clear cells, and focal keratinization with the presence of ghost cells. The tumor harbors a wild-type genotype for BRAF and KRAS. Activation of the Wnt/beta-catenin signaling pathway occurs in AA, primarily attributed to CTNNB1 gene mutations, which have been described in 25% of investigated cases. This study aimed to expand the genetic characterization of AA by investigating variants in 22 oncogenes and tumor suppressor genes commonly mutated in solid tumors. Six AA samples were sequenced via next-generation sequencing (NGS) using a 22-gene panel, including AKT1, ALK, BRAF, CTNNB1, EGFR, ERBB2, ERBB3, ESR1, FOXL2, GNA11, GNAQ, IDH1, IDH2, KRAS, KIT, MET, NRAS, PDGFRA, PIK3CA, RAF1, RET, and TP53. CTNNB1 mutations were identified in 4 of the 6 cases (67%), including previously described variants (p.Ser33Cys and p.Gly34Arg) as well as novel variants (p.Leu31Leu and p.Gln68*), reinforcing the involvement of the Wnt/beta-catenin signaling pathway in AA pathogenesis. In two cases, CTNNB1 variants co-occurred with variants in TP53 or in ERBB2 and PIK3CA, suggesting potential secondary oncogenic events. Reinforcing the distinct molecular identity of AA compared to ameloblastoma and adenomatoid odontogenic tumor, the absence of BRAF p.Val600Glu and KRAS p.Gly12Val/Arg mutations - recurrent in the aforementioned entities - was observed. Notably, no variants were detected in two cases. Our findings provide further evidence for the classification of AA as a distinct tumor entity. The identification of previously described CTNNB1 variants, as well as novel genetic variants, contributes to a better characterization of the molecular profile of AA. Future studies are needed to investigate variants in other genes in cases with a wild-type genotype.