The Mutational Profile of Unicystic Ameloblastoma

Abstract

BRAF V600E is the most common mutation in conventional ameloblastoma (AM) of the mandible. In contrast, maxillary AMs appear to harbor more frequently RAS, FGFR2, or SMO mutations. Unicystic ameloblastoma (UAM) is considered a less aggressive variant of ameloblastoma, amenable to more conservative treatment, and classified as a distinct entity. The aim of this study was to characterize the mutation profile of UAM ( n = 39) and to compare it to conventional AM ( n = 39). The associations between mutation status and recurrence probability were also analyzed. In the mandible, 94% of UAMs (29/31, including 8/8 luminal, 6/8 intraluminal, and 15/15 mural subtypes) and 74% of AMs (28/38) revealed BRAF V600E mutations. Among the BRAF wild-type cases, 1 UAM showed a missense SMO mutation (p.L412F), whereas 2 NRAS (p.Q61R), 2 HRAS (p.Q61R), and 2 FGFR2 (p.C383R) activating mutations were identified in AM. Of the 3 maxillary UAMs, only 1 revealed a BRAF V600E mutation. Taken together, our findings demonstrate high frequency of activating BRAF V600E mutations in both UAM and AM of the mandible. In maxillary UAMs, the BRAF V600E mutation prevalence appears to be lower as was shown for AM previously. It could therefore be argued that UAM and AM are part of the spectrum of the same disease. AMs without BRAF V600E mutations were associated with an increased rate of local recurrence ( P = 0.0003), which might indicate that routine mutation testing also has an impact on prognosis.

Ultra‐frequent HRAS p.Q61R somatic mutation in canine acanthomatous ameloblastoma reveals pathogenic similarities with human ameloblastoma

“…Despite the pathological similarities between CAA and AM, the data show a notable difference in the frequency of the HRAS p.Q61R mutation. Contrasting with our findings, only 20% of AM harbour RAS mutations, with HRAS p.Q61R occurring with a frequency of 6% or less (Figure ) . Similarly, while two‐thirds or more of AM harbour a BRAF p.V600E mutation, the results of this and previous studies show that homologous mutations are either not present in CAA or occur at low frequency.…”

“…Recent discoveries have shown that the majority of human ameloblastomas (AM) are driven by mutually‐exclusive BRAF , HRAS , NRAS , KRAS or FGFR2 mutations that activate the MAPK pathway regulating cell survival . Co‐occurring SMO mutations that alter the Hedgehog signalling pathway to regulate cell fate have also been detected, especially in maxillary tumours .…”

“…Comparison of oncogenic mutations in canine acanthomatous ameloblastoma (CAA) (N = 40) and ameloblastomas (AM) (N = 113) based on the results of this and previous studies, discriminating based on anatomical tumour location (ie, maxilla vs mandible). (A) HRAS or BRAF mutations and (candidate gene) wild‐type (WT) in CAA (maxilla N = 13; mandible N = 27).…”

“…This study focused exclusively on candidate genes known to be mutated in AM, and it is possible that other oncogenic or tumour suppressor genes could be mutated in CAA, including non‐coding RNAs . Furthermore, these data do not ascertain whether the HRAS p.Q61R mutation acts as a primary or secondary oncogenic driver in CAA.…”

“…10 Recent discoveries have shown that the majority of human ameloblastomas (AM) are driven by mutually-exclusive BRAF, HRAS, NRAS, KRAS or FGFR2 mutations that activate the MAPK pathway regulating cell survival. 9,[11][12][13][14][15] Co-occurring SMO mutations that alter the Hedgehog signalling pathway to regulate cell fate have also been detected, especially in maxillary tumours. 12,13 Both pathways are mutated in various cancers and have been targeted for therapy, making them of particular interest in personalized oncology.…”