Date of Award

January 2012

Document Type

Open Access Thesis

Degree Name

Master of Public Health (MPH)

Department

School of Public Health

First Advisor

Susan T. Mayne

Second Advisor

Andrew T. DeWan

Abstract

Background: Lung cancer is one of the most common cancers worldwide and has the highest cancer-related mortality rate. Epidemiologic studies, including the Environment and Genetics in Lung Cancer Etiology (EAGLE) study, have reported that frequent consumption of quercetin-rich foods is inversely associated with lung cancer incidence. Although experimental studies suggest that quercetin intake might modulate microRNA (miR) expression, this mechanism has not been fully examined. We investigated this hypothesis in lung carcinogenesis using EAGLE lung cancer tissues.

Methods: miR expression data were measured by a custom-made array in formalin-fixed paraffin-embedded tissue samples from 264 lung cancer cases (144 adenocarcinomas and 120 squamous cell carcinomas). Intake of quercetin-rich foods was derived from a food-frequency questionnaire. Individuals were categorized into sex-specific tertiles of quercetin-rich food intake. In individual-miR-based analyses, we compared the expression of miRs (n=198) between lung cancer cases consuming high-versus-low quercetin-rich food intake using multivariate ANOVA tests. In family-miR-based analyses, we grouped individual miRs into biologically functional families and conducted analyses using Functional Class Scoring (FCS). We accounted for multiple testing using 10,000 global permutations (significance at p-valueglobal <0.10). All analyses were conducted separately by histology (adenocarcinoma and squamous cell carcinoma) and by smoking status (former and current smokers).

Results: Family-based analyses showed that a quercetin-rich diet strongly differentiated miR expression profiles of the let-7 family among adenocarcinomas (p-valueFCS <0.001). Other significantly differentiated miR families included miR-146, miR-26, and miR-17 (p-valuesFCS <0.05). In the individual-based analyses, we found that among former and current smokers with adenocarcinoma, 33 miRs were observed to be differentiated between highest and lowest quercetin-rich consumers (23 expected by chance; p-valueglobal = 0.047). Additionally, we identified 25 miRs to be differentially expressed among former smokers with adenocarcinoma (22 expected by chance; p-valueglobal =0.076).

Conclusions: We observed differential expression of key biologically functional miRNAs between high-versus-low consumers of quercetin-rich foods in adenocarcinoma cases. Our findings, the first of this kind, warrant confirmation from larger studies.

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This is an Open Access Thesis.

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