Abstract
Abstract Adenomatoid odontogenic tumor (AOT) is a benign encapsulated epithelial odontogenic tumor that shows indolent clinical behavior and predilection for young individuals. We have recently reported in a few AOT cases mutations in KRAS, which is a proto-oncogene frequently mutated in cancer types such as lung, pancreas and colorectal adenocarcinomas. We aimed to assess KRAS mutations in the hotspot codons 12, 13 and 61 in a large cohort of AOT samples and to test the association of these mutations with clinical (patients’ age, tumor site, tumor size, follicular or extrafollicular subtypes) and histopathological parameters. A convenience sample of 38 central AOT cases was included in the study. KRAS codon 12 mutations were assessed by TaqMan allele-specific qPCR (p.G12V/R) and/or Sanger sequencing, and codon 13 and 61 mutations were screened by Sanger. Histological tumor capsule thickness was evaluated by morphometric analysis. In addition, the phosphorylated form of the MAPK downstream effector ERK1/2 was investigated. Statistical analysis was carried out to test the association of KRAS mutations with clinicopathological parameters. KRAS c.35G>T mutation, leading to p.G12V, was detected in 15 cases. A novel mutation in AOT, c.34G>C, leading to p.G12R, was detected in 12 cases and the other 11 were wild-type. Codon 12 mutations were not associated with the clinicopathological parameters tested. RAS mutations are known to activate the MAPK pathway and we show AOTs express phosphorylated ERK1/2. In conclusion, a high proportion of AOT (27/38, 71%) have KRAS codon 12 mutations, which occur independently of the clinicopathological features evaluated. Collectively, these findings indicate that KRAS mutations and MAPK pathway activation is a common feature of AOT and some cancer types. Although it is unclear why different codon 12 alleles occur in different disease contexts and the complex interactions between tumor genotype-phenotype need clarification, on the basis of our results the presence of KRAS p.G12V or p.G12R can favor the AOT diagnosis in challenging oral neoplasm cases.Acknowledgements: This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - Brazil (CAPES) - Finance Code 001 and CNPq/Brazil. Citation Format: Carolina C. Gomes, Bruna P. Coura, Vanessa F. Bernardes, Silvia F. de Sousa, Josiane A. França, Nubia B. Pereira, Helder A. Pontes, Aline C. Batista, Danyel E. Perez, Ricardo C. Albuquerque, Lelia B. de Souza, Manoela D. Martins, Marina G. Diniz, Ricardo S. Gomez. KRAS mutations drive adenomatoid odontogenic tumor and are independent of clinicopathological features [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4663.
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