The molecular epidemiology of ovarian cancer: Protein concentrations, epigenetic modification, and polymorphisms. Examples in cancer etiology, prognosis, and treatment

This dissertation consists of three projects---each focused on different molecules and mechanisms of alteration---but united as an investigation into the molecular epidemiology of ovarian cancer. Topics within three broad molecular areas are studied that evaluate complementary aspects of cancer epidemiology: (1) variation of circulating protein concentrations and cancer risk, (2) epigenetic modification by DNA methylation and tumor progression, and (3) functional genetic polymorphisms and patient response to treatment and survival.; The first project evaluates the role of individual variation in protein concentration and cancer susceptibility. A systematic review and meta-analysis of the epidemiological literature was conducted to estimate the association between circulating insulin-like growth factor binding protein-3 (IGFBP-3) and cancer. Forty-three publications were included. No significant association was seen (OR: 1.00, 95% CI: 0.86-1.17). However, when adjustment for IGF-I was included, a marginal relationship between high levels of IGFBP-3 and reduced cancer risk was suggested (OR: 0.84, 95% CI: 0.69-1.02).; The second project evaluates an epigenetic modification, methylation, and complements the first project by assessing another molecule of the IGF system, insulinlike growth factor-II (IGF-II). Seven methylation specific PCR (MSP) assays were developed in three promoter regions (P2, P3, and P4) of the IGF-II gene. Methylation was found to vary: 19.3% in P2A, 45.6% in P2B, 50.9% in P2C, 48.4% in P3A, 13.1% in P3B, 5.1% in P4A, and 6.1% in P4B. Methylation in any of the 3 P2 assays was associated with high tumor grade (p=0.043), suboptimal debulking (p=0.036), and disease progression (HR=1.77, 95%CI: 1.12-2.79). When comparing promoter combinations, a pattern involving P2 and P3 methylation was revealed; patients with unmethylated P2 and methylated P3 were less likely to have disease progression (HR=0.34, 95% CI: 0.15-0.79) than those with methylated P2 and unmethylated P3. Therefore, epigenetic modification of IGF-II may play a role in ovarian cancer prognosis.; The final project studies three functional genetic polymorphisms in the glutathione S-transferase (GST) family of enzymes and their association with response to treatment and survival. Patients were genotyped for three GST genes: GSTM1, GSTT1, and GSTP1. A significant reduction in the risk of disease progression was revealed for GSTM1 null patients (HR: 0.65, 95% CI: 0.43-0.99). Patients with GSTM1 null plus GSTP1 reduced function genotypes also had better progression free survival (HR: 0.42, 95% CI: 0.24-0.75). Further, these survival effects were more evident among subgroups of patients who received specific chemotherapeutic agents: platinum, taxol, and cyclophosphamide. Therefore, individual variations in the ability to metabolize chemotherapeutic agents by GST enzymes due to functional polymorphisms may contribute to differences in ovarian cancer survival.; The first project analyzes existing epidemiological literature. Both of the second two projects include molecular analyses conducted in the laboratory of Dr. Herbert Yu, using DNA extracted from tumors from a clinical cohort of women with primary invasive epithelial ovarian cancer assembled and followed prospectively by collaborators at the University of Turin in Italy. Together, these three projects evaluate a range of components in the field of the molecular epidemiology of epithelial ovarian cancer.