The landscape of genetic alterations in ameloblastomas relates to clinical features

Abstract

Ameloblastoma is a mostly benign, but locally invasive odontogenic tumor eliciting frequent relapses and significant morbidity. Recently, mutually exclusive mutations in BRAF and SMO were identified causing constitutive activation of MAPK and hedgehog signaling pathways. To explore further such clinically relevant genotype-phenotype correlations, we here comprehensively analyzed a large series of ameloblastomas (98 paraffin block of 76 patients) with respect to genomic alterations, clinical presentation, and histological features collected from the archives of three different pathology centers in France, Germany, and Turkey. In good agreement with previously published data, we observed BRAF mutations almost exclusively in mandibular tumors, SMO mutations predominantly in maxillary tumors, and single mutations in EGFR, KRAS, and NRAS. KRAS, NRAS, PIK3CA, PTEN, CDKN2A, FGFR, and CTNNB1 mutations co-occurred in the background of either BRAF or SMO mutations. Strikingly, multiple mutations were exclusively observed in European patients, in solid ameloblastomas and were associated with a very high risk for recurrence. In contrast, tumors with a single BRAF mutation revealed a lower risk for relapse. We here establish a comprehensive landscape of mutations in the MAPK and hedgehog signaling pathways relating to clinical features of ameloblastoma. Our data suggest that ameloblastomas harboring single BRAF mutations are excellent candidates for neo-adjuvant therapies with combined BRAF/MEK inhibitors and that the risk of recurrence maybe stratified based on the mutational spectrum.

Keywords: Ameloblastoma; Genotype-phenotype correlation; Hedgehog signaling; MAPKinase signaling; Mutation-based risk stratification; Mutational risk profiling.

Fig. 1

Histologic features of ameloblastomas analyzed in this study. a Follicular ameloblastoma showing tumor islands with peripheral columnar cells and stellate reticulum-like cells (H&E, magnification ×100). b Plexiform ameloblastoma showing long anatomizing cords of ameloblastic epithelium (H&E, magnification ×100). c Intraluminal unicystic ameloblastoma lined by ameloblastic epithelium with luminal projections, no evidence of stromal invasion (H&E, magnification ×100). d Peripheral ameloblastoma showing tumor islands just underneath the oral mucosal epithelium (H&E, magnification ×100)

Fig. 2

Overview of genomic alterations in ameloblastomas. Distribution of mutated genes with regard to anatomic location. Colored boxes indicate the presence of mutations in the genes listed on the left; columns indicate the respective cases. Prevalence of gene mutations

Fig. 3

Distribution of mutations with regard to geographic regions. TK cases from Turkey, G + F cases from Germany and France