BRAF p.Val600Glu Mutations Are Not Detected in Adenomatoid Odontogenic Tumors.

Abstract

The adenomatoid odontogenic tumor (AOT) is a benign, encapsulated odontogenic tumor characterized by slow growth and indolent behavior. AOT shows mitogen-activated protein kinase/ERK pathway activation, and KRAS p.Gly12Val or p.Gly12Arg mutations occur in 70% of cases. The molecular events underlying the pathogenesis of the other 30% of cases remain unclear. The BRAF p.Val600Glu mutation was reported by a single study in 2 AOT cases, 1 of which also harbored KRAS p.Gly12Val. Given that BRAF p.Val600Glu has not been previously detected in AOT and that BRAF and KRAS mutations are mutually exclusive, we aimed to assess BRAF p.Val600Glu irrespective of KRAS mutational status to explore the potential involvement of BRAF mutations in AOT pathogenesis and the co-occurrence of BRAF and KRAS mutations. Whereas KRAS codon 13 and 61 hotspot mutations have not been previously detected in AOT, KRAS codon 146 hotspot mutations have been investigated in a few AOT cases to date. Therefore, we further sequenced KRAS codon 146 in KRAS codon 12 wild-type cases. A total of 29 AOT samples, including 21 KRAS codon 12 mutation-positive cases and 8 wild-type cases, were evaluated for the BRAF p.Val600Glu pathogenic mutation using allele-specific qPCR and/or Sanger sequencing. In addition, KRAS codon 146 was Sanger sequenced in 4 out of 29 samples. BRAF p.Val600Glu was not detected in any of the 29 AOT cases evaluated, either alone or as a comutation with KRAS mutations. All codon 12 wild-type cases were wild-type for KRAS codon 146 mutations. These findings reinforce that KRAS codon 12 mutant alleles predominate in the context of AOT tumorigenesis, whereas BRAF p.Val600Glu does not constitute a molecular feature of this tumor and the presence of the BRAF mutation does not support the diagnosis of AOT in challenging cases. In addition, the results further strengthen the notion that BRAF and KRAS mutations are mutually exclusive events.