| Despite significant improvement in locoregional control in the contemporary era, nasopharyngeal carcinoma (NPC) patients still suffer from a significant risk of distant metastasis (DM). Thus, developing methods to better identify and treat NPC patients at risk of DM is of paramount importance. MicroRNAs (miRNAs) have been shown to provide insight into both the biology and clinical behaviour of human cancers; hence, this thesis aims to characterize both the biological function and the prognostic utility of miRNAs in NPC.;First, miR-375 was identified as the most consistently and significantly down-regulated miRNA in head and neck cancer samples (including NPC) analyzed. Functional experiments confirmed a tumour suppressor role for miR-375. A novel target of miR-375, metadherin, was identified as a likely mediator of these effects; possibly through activation of the PI3K/Akt pathway. In addition, a clinical relationship was observed wherein NPC patients whose tumours expressed high metadherin transcript levels had an increased risk of developing distant metastases.;Next, a 4-miRNA expression signature associated with risk of DM was identified in a training set of 125 NPC patients (HR 8.25; p<0.001). This signature was subsequently confirmed to be predictive of DM in an independent validation set (n=121, HR 3.2; p=0.01). Moreover, the 4-miRNA signature was observed to add to the prognostic value of the currently utilized clinical staging system. In addition, pathway enrichment analysis identified a potential role for these miRNAs in cell cycle regulation.;Finally, a pilot project was undertaken which established the feasibility and utility of molecular inversion probe (MIP) technology for the detection of copy-number alterations (CNAs) in small archival NPC biopsy samples.;In conclusion, the insights presented herein provide both clinical and biological insights into NPC, which will advance us closer to the goal of personalized management of this disease and improve treatment and outcome for future NPC patients. |
