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Abstract
Epithelial ovarian cancer is the most lethal gynaecological malignancy, largely due to the absence of an effective diagnostic test for early stage disease. A better understanding of the early stages of ovarian carcinogenesis is critical for the development of new diagnostic strategies for early stage curable disease. Determining the molecular pathogenesis of high-grade serous ovarian carcinomas (HGSOC), the most common type of ovarian cancer, is particularly challenging, as few women present with early stage disease, and there is no defined premalignant or low-grade precursor. Women with strong family histories of breast/ovarian cancer, including those with mutations in the breast cancer susceptibility genes BRCA1/2 are at high risk of developing HGSOC, and frequently undergo prophylactic bilateral salpingo-oophorectomy to prevent its development. The ovarian surface epithelium (OSE) from these women exhibits cancer-associated morphological and/or phenotypical changes, and provides an opportunity to study early HGSOC pathogenesis. The aim of this study was to use tissue from BRCA1/2 mutation positive women to further characterise the early stages of HGSOC. Ovarian surface epithelial cells from women with and without family histories of breast/ovarian cancer were collected and cultured in order to investigate culture and molecular differences between them. In culture, the OSE from women with strong family histories displayed altered proliferation and survival characteristics, demonstrated by a shorter time to confluence at passage 1, a higher yield and a higher percentage of cells surviving at each passage. We then applied a candidate approach to detecting gene expression and methylation alterations in the family history OSE. Gene expression analysis revealed a cancer-related overexpression of BTAK, a cancer-associated kinase. The expression of two other candidate genes (ALDH1 and HOXA9) was altered in ovarian cancer cell lines and HGSOC, but not in the family history OSE. No gene methylation alterations were detected in the family history compared to the control OSE. Overall, the results presented in this thesis demonstrate that OSE from women with a family history of breast/ovarian cancer, including those with mutations in BRCA1/2 are undergoing growth and molecular changes that may be cancer related.