Abstract 88: Recurrent KRAS G12V pathogenic mutation in adenomatoid odontogenic tumors
Authors: Gomes Carolina C. , Sousa Silvia F. , Menezes Grazielle F. , Pereira Thais S.F. , Moreira Rennan G. , Duarte Alessandra P. , Castro Wagner H. , Villacis Rolando A.R. , Rogatto Silvia R. , Diniz Marina G. , Gomez Ricardo S. 
Published: July 2016

Abstract
The adenomatoid odontogenic tumor (AOT) is a benign tumor of uncertain pathogenesis. Schimmelpenning syndrome is characterized by sebaceous nevi, which occurs often on the face, associated with variable ipsilateral abnormalities of the central nervous system, including ocular and skeletal abnormalities. It results from postzygotic autosomal dominant HRAS or KRAS lethal mutations that survive by somatic mosaicism. RAS genes mutations were previously reported in lesional tissue (including nevus sebaceous) of a patient, but not in normal skin or blood leukocytes, consistent with a somatic mosaic state. Interestingly, a case of multiple AOT was reported in a Schimmelpenning syndrome patient, which prompted us to evaluate RAS genes mutations, as well as 207 cancer genes mutations in a sample of one AOT from one Schimmelpenning syndrome patient having multiple tumors (index patient). We used the Ion AmpliSeqTM Cancer Hotspot Panel to interrogate these mutations by targeted next generation sequencing. We further included 3 sporadic AOT samples to assess if they shared similar mutations with the sample of the index patient. Additionally, molecular karyotyping analysis was performed in the index patient sample, as well as in one sporadic AOT sample by using a high-density whole genome array platform (Cytoscan® HD Array). The pathogenic KRAS G12V mutation was detected in the index patient sample of AOT, and in 2 out of 3 samples evaluated. No other pathogenic mutation was detected in the AOT samples. TaqMan® Mutation Detection probes specific to the c.35G&gt;T KRAS gene substitution and/or Sanger sequencing were used to validate the mutation in all samples and in a panel of 4 additional sporadic AOT samples. A total of 7 out of 8 AOT samples showed the KRAS pathogenic mutation. We found a few copy number variations (CNVs), most of them common variations or alterations not encompassing genes. Loss of 7p15.3 encompassing the IGF2BP3 gene was detected in the sporadic AOT sample. In conclusion, we report for the first time the recurrent activating KRAS G12V mutation in a high proportion of investigated AOTs, while no other pathogenic mutation interrogated was detected. The importance of the 7p15.3 loss in the aetiopathogenesis of this tumor type remains to be established. Despite the benign nature of AOT, our results shed some light in future molecular targeted-therapy for the lesion. Supported by: CNPq, CAPES and FAPEMIG (Brazil).
Citation Format: Carolina C. Gomes, Silvia F. Sousa, Grazielle F. Menezes, Thais S.F. Pereira, Rennan G. Moreira, Alessandra P. Duarte, Wagner H. Castro, Rolando A.R. Villacis, Silvia R. Rogatto, Marina G. Diniz, Ricardo S. Gomez. Recurrent KRAS G12V pathogenic mutation in adenomatoid odontogenic tumors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 88.