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UBC Theses and Dissertations

Circulating microRNAs as biomarkers for early cancer detection MacLellan, Sara Ann

Abstract

Cancer is a major cause of death worldwide. Patients diagnosed at an early stage have an improved prognosis and therefore efforts have been made into the development of methods to detect tumors at their earliest stages. MicroRNAs (miRNAs) are non-coding RNAs that negatively regulate gene expression by interfering with the translation of target mRNAs. Studies have found that miRNAs are present at stable levels in the circulation and that they are differentially expressed in patients with various diseases. In this thesis we used qRT-PCR to assess the utility of 742 serum miRNAs as biomarkers for early cancer detection. In aim 1 we examined the levels of serum miRNAs in patients with high-risk oral lesions. We identified five miRNAs that are significantly deregulated in the serum of these patients compared to demographically matched, non-cancer controls. Additionally, these miRNAs correspondingly decreased or increased after surgical resection of the lesion. In aim 2 we examined the effect of hemolysis, fasting, and smoking on the serum miRNA levels of healthy individuals. We also compared serum miRNA profiles of samples taken from healthy individuals over different time periods. We found that mechanical hemolysis of blood samples simulating blood drawing can significantly alter serum miRNA quantification and should be taken into consideration when identifying endogenous controls and candidate biomarkers for circulating miRNA studies. Fasting, smoking, and a time period up to 17 months between samples were demonstrated to not have a significant effect on the overall serum miRNA profiles of healthy individuals. In aim 3 we compared the miRNA profiles of paired samples collected during surgery from the same patient from a) pulmonary venous effluent draining the tumor vascular bed (tumor associated samples) and b) systemic arterial blood to identify lung adenocarcinoma biomarkers. We found 35 miRNAs that were significantly up-regulated in tumor-associated serum samples. However, when we tested the candidate miRNAs in cancer versus non-cancer peripheral venous blood samples they were not significantly differentially expressed. The results presented in this thesis demonstrate the need for standardized protocols for circulating miRNA studies and provide evidence for the utility of serum miRNAs as biomarkers of disease.

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