UBC Theses and Dissertations

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UBC Theses and Dissertations

Novel biomarkers for early cancer detection and screening Li, Gerald


Early detection and screening have reduced mortality from many cancers, but there remains a need for improved biomarkers of risk. Cytometric DNA ploidy analysis has been used for the detection, treatment, and management of many cancers, but greater clinical utility would come with increased accuracy. Improvements to ploidy-based screening might come from adding complementary biological information. The first aim combined ploidy with the additional biological information provided by malignancy associated changes as detected by automated nuclear morphometry. In 2249 sputum samples, the resultant biomarker, the Combined Score (CS), correlated with lung cancer risk factors like dysplasia grade, age, smoking status, and p53 and Ki-67 immunostaining. CS is a minimally invasive tool for risk assessment for the presence of precancerous lung lesions and could enrich chemoprevention trials with subjects likely to have high-risk dysplasias. The second aim complemented ploidy with biological information provided by immunocytochemistry in a double staining procedure. Testing 49 cervical cytology brushings showed addition of Ki-67 immunostaining to distinguish abnormal cells from normal cycling cells did not improve ploidy’s ability to separate high- and low-grade dysplasias. Nevertheless, double staining with Feulgen thionin and immunocytochemistry was shown to be technically feasible, even with antigen retrieval, and might be applicable to other immunocytochemical stains. Motivated by the ability to combine ploidy with immunocytochemistry, the third aim investigated techniques for biomarker discovery pertinent to cervical dysplasia development. Cervical squamous epithelium consists of a continuum of differentiating cells and carcinogenesis disrupts this cell maturation program. Gene expression differences between the basal and superficial epithelial layers and across various grades of dysplasia could catalyze the discovery of novel biomarkers through a better understanding of carcinogenesis. Microdissection and expression microarray analysis of molecular fixative preserved cervical biopsies resulted in the immunohistochemistry validation of four candidate targets showing correlation with dysplasia grade. This work underscores the importance and potential of accounting for heterogeneity within stratified squamous epithelium and constitutes the first report of successful gene expression microarray analysis of microdissected epithelial layers from molecular fixative preserved paraffin-embedded cervical specimens. Ploidy combined with digital morphometry and immunocytochemistry can generate useful biomarkers of early squamous cell carcinomas.

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