The first step towards the prevention of cancer is to develop an in-depth understanding of tumourigenesis and the molecular basis of malignant transformation. What drives tumour initiation? Why do most benign tumours fail to metastasize? Oncogenic mutations, previously considered to be the hallmark drivers of cancers, are reported in benign cysts and tumours, including those that have an odontogenic origin. Despite the presence of such alterations, the vast majority of odontogenic lesions are benign and never progress to the stage of malignant transformation. As these lesions are likely to develop due to developmental defects, it is possible that they harbour quiet genomes. Now the question arises - do they result from DNA replication errors? Specific candidate genes have been sequenced in odontogenic lesions, revealing recurrent BRAF mutation in the case of ameloblastoma, KRAS mutation in adenomatoid odontogenic tumours, PTCH1 mutation in odontogenic keratocysts, and CTNNB1 (Beta-catenin) mutation in calcifying odontogenic cysts. Studies on these benign and rare entities might reveal important information about the tumorigenic process and the mechanisms that hinder/halt neoplastic progression. This is because the role of relatively common oncogenic mutations seems to be context dependent. In this review, each mutation signature of the odontogenic lesion and the affected signalling pathways are discussed in the context of tooth development and tumorigenesis. Furthermore, behavioural differences between different types of odontogenic lesions are explored and discussed based on the molecular alteration described. This review also includes the employment of molecular results for guiding therapeutic approaches towards odontogenic lesions.

BackgroundThe erbB receptors and their ligands are involved in the pathogenesis and progression of oral squamous cell carcinoma (OSCC). Although EGFR and Her-2 are frequently overexpressed in OSCC, few studies evaluated these proteins in saliva and their association with the tumor, which may represent potential usefulness in a clinical setting.MethodsThe levels of EGFR, Her-2, and EGF were evaluated in saliva of 46 patients with OSCC before and after the surgical removal of the lesion, as well as in matched healthy controls. The relationship of salivary levels and EGFR and Her-2 immunoexpression in tumor samples with clinicopathological features was analyzed.ResultsEGFR and Her-2 salivary levels did not show difference between to pre-surgery and control groups, however, both demonstrated an increase after surgical removal of the tumor. No association was detectable among receptor salivary levels, tissue expression and clinicopathological features. EGF levels in pre-surgery group were significantly lower when compared to the control group.ConclusionsEGFR and Her-2 were not considered to be valuable salivary tumor markers in OSCC, however, lower levels of EGF in saliva may suggest a higher susceptibility for OSCC development.

Letter to the editor Recurrent KRAS G12V pathogenic mutation in adenomatoid odontogenic tumours Dear Editor, The adenomatoid odontogenic tumour (AOT) is a non-aggressive encapsulated tumour, being usually diagnosed in association with an unerupted permanent maxillary canine [1,2]. There are scarce reports of multiple AOTs [3-5] and a patient with Schimmelpenning syndrome (SS) with AOT was reported [6]. SS is characterized by sebaceous nevi, associated with ipsilateral abnormalities of the central nervous system, resulting from postzygotic autosomal dominant HRAS or KRAS lethal mutations that survive by somatic mosaicism [7]. RAS 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 mosaicism [7]. We evaluated one AOT sample from a SS patient having multiple AOTs (index patient) and two sporadic AOTs (samples #1 and #2) for mutations in a panel of 50 oncogenes and tumour suppressor genes, including RAS family, by using Ion AmpliSeq TM Cancer Hotspot Panel v2 (Life Technologies, Carlsbad, USA). After filtering by missense variants, candidate variants from the panel were defined as those pathogenic variants in regions with a depth greater than X500 and frequency greater than 5%. Only KRASc.35G > T (KRASG12V) fit this criteria, and was validated by TaqMan Ò Mutation Detection Assay using the probes KRAS_476_mu and KRAS_rf (Applied Biosystems, Foster City, USA). We further interrogated the KRASG12V mutation in six extra AOTs (samples #3-8) by the TaqMan Ò Assay. This KRAS mutation was detected in the three samples, as well as in four (samples #3, #4, #5 and #7) out of six additional samples. The mutation was validated by Sanger sequencing (Fig. 1). No other pathogenic mutation interrogated was detected. Blood leukocytes from the index patient were negative for KRASG12V mutation. To determine the specificity of the KRASG12V mutation in the context of odontogenic tumours, we evaluated three ameloblastomas, two dentinogenic ghost cell tumours and two normal oral mucosa samples using the TaqMan Ò Assay, being all negative for the mutation. Constitutively activation of the MAPK pathway by BRAFV600E mutation was reported in ameloblastoma [8-10], and in ameloblastic carcinoma [11]. We describe a recurrent oncogenic mutation in an upstream activator of MAPK, KRAS, in AOT. RAS mutations are found in 30% of human cancers and 80% of KRAS mutations occur at codon 12, being highly frequent in lung adenocarcinoma, pancreatic and colon carcinomas [12]. In our series, seven out of nine AOTs exhibited the KRASG12V mutation. The KRAS mutation was identified in the index patient sample and in sporadic AOTs, a candidate to driver mutation in these lesions. Driver mutations confer growth advantage to tumour cells and are positively selected during cancer evolution [13].

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