UNRAVELING THE TRANSCRIPTOME OF ODONTOGENIC TUMORS

Odontogenic tumors, represent 31% of the oral tumors in children, are phenotypically diverse neoplasms of tissues that are responsible for tooth formation. Ameloblastoma and keratocystic odontogenic tumor, both believed to be derived from the odontogenic epithelium, constitute more than 50% of odontogenic tumors. Although both are usually slow-growing, they are locally invasive and have a recurrence rate as high as 50-80%. The lack of established adjunctive therapy means that surgical removal of the tumor with extensive margins to ensure complete excision remains the primary treatment of choice, resulting in significant morbidity. Tremendous advances are being made in the understanding of molecular mechanisms and pathways involved in tumorigenesis, improving diagnostic and therapeutic approaches. Most research on odontogenic tumors focused on candidate-genes with only a handful of studies employing whole genome and transcriptome approaches. Another limitation is the question of what normal tissue is most biologically-relevant for gene expression comparison with odontogenic tumors. Obtaining and characterizing the gene expression profile of odontogenic epithelium at different stages of differentiation will provide a biologically-relevant reference for comparison. This study aims to bridge the current gap of knowledge in odontogenic tumor biology by characterizing the transcriptome of ameloblastoma and KCOT which up till this point has not been fully explored. The results showed that ameloblastoma separated into 2 distinct molecular clusters that were associated with 2 types of odontogenic tissue. Importantly, we found that 9/10 of the samples in the pre-secretory cluster were of the follicular type while 6/7 of the samples in the odontoblast cluster were of the plexiform type. Analysis of differential gene expression revealed alteration of common pathways in both clusters including cell cycle regulation, inflammatory and MAPkinase. Similarly, 2 distinct molecular subtypes of KCOT were found with several canonical inflammatory pathways activated in both subtypes of KCOT. Of note, the AKT pathway was activated in one subtype while MAPkinase pathway was activated in the other. Our results are suggestive of underlying molecular heterogeneity of odontogenic tumors which could indicate different receptiveness to treatment protocols. These findings have implications in the tailored use of chemotherapeutic agents or other treatment modalities.Doctor of Philosoph