Expanding the Molecular Characterization of Adenoid Ameloblastoma by Assessing a Panel of Oncogenes and Tumor Suppressor Genes.

Adenoid ameloblastoma (AA) is a rare epithelial odontogenic tumor microscopically characterized by ameloblastoma-like epithelium, duct-like structures, epithelial whorls, cribriform architecture, and dentinoid matrix. Wnt/β-catenin activation, usually by CTNNB1 mutations, is thought to characterize AA, which are BRAF and KRAS wild type. The present study aimed to expand the genetic characterization of AA by interrogating variants at several sites known to be linked to solid tumor pathogenesis. Six AA samples were sequenced at an unprecedented sequencing depth using a 22-gene panel including oncogenes and tumor suppressor genes commonly mutated in solid human tumors, namely AKT1, ALK, BRAF, CTNNB1, EGFR, ERBB2, ERBB3, ESR1, FOXL2, GNA11, GNAQ, IDH1, IDH2, KRAS, KIT, MET, NRAS, PDGFRA, PIK3CA, RAF1, RET, and TP53. Reinforcing the distinct molecular identity of AA, absence of BRAF p.Val600Glu and KRAS p.Gly12Val/Arg mutations was observed. CTNNB1 mutations were identified in 4 of 6 cases (67%), including previously reported variants (p.Ser33Cys and p.Gly34Arg) as well as novel ones (p.Leu31Leu and p.Gln68∗), supporting the involvement of the Wnt/β-catenin signaling pathway in AA pathogenesis. In 2 cases, CTNNB1 variants co-occurred with either TP53 or ERBB2 and PIK3CA variants, suggesting potential secondary oncogenic events. Notably, in 2 cases, no variants were detected. Our findings provide further evidence for AA classification as a separate tumor entity. The identification of previously reported CTNNB1 and novel genetic variants contributes to better characterization of the molecular profile of AA. Future studies are required to interrogate variants in other genes in wild-type cases.