Association of GLI1 overexpression with acanthomatous change in ameloblastoma

Mutations in mitogen-activated protein kinase (MAPK) and sonic hedgehog (SHH) pathways are the most common genetic changes reported in ameloblastomas. This study tried to find the mutational landscape of ameloblastomas in Taiwan and clarify the role of SHH pathway in the pathogenesis of ameloblastoma.

Sanger sequencing of the mutation hot spots in BRAF, KRAS, FGFR2, and SMO genes were performed in 77 ameloblastomas. Real-time RT-PCR and double immunohistochemistry were performed for measurement of glioma-associated oncogene homolog 1 (GLI1) mRNA expression levels and detection of GLI1 protein and cytokeratin 17 (CK17) expressions in 30 ameloblastomas, respectively.

BRAF V600E mutations were identified in 77.9 % (60/77) ameloblastomas. No FGFR2 (C382R), KRAS (G12R), or SMO (L412F or W535L) mutation could be identified in this cohort. GLI1 mRNA expression in ameloblastoma was significantly associated with older age of the patient, recurrent tumor, and keratin formation. Furthermore, significantly higher GLI1 mRNA expression level in acanthomatous ameloblastomas than controls and other histological subtypes of ameloblastomas, indicating a positive correlation between the GLI1 mRNA expression level and keratin formation in ameloblastomas. The double immunostains demonstrated the juxtaposition, instead of co-localization, of GLI1 and CK17 expression in the ameloblastoma tumor nest, suggesting a paracrine control of keratin production by the GLI1 protein in ameloblastoma.

The concomitant activation of both the MAPK and SHH pathways is frequently found in ameloblastomas. GLI1 may stimulate the keratin production through a paracrine regulatory mechanism. SHH pathway is most likely a later event in the pathogenesis of ameloblastomas.