<> "The repository administrator has not yet configured an RDF license."^^ . <> . . "Tumor Evolution and Heterogeneity in High-Grade Serous Ovarian Cancer"^^ . "Ovarian cancer (OC) is a heterogeneous disease and can be delineated into five major histological subtypes. In 2018, the disease caused 184,799 deaths worldwide, where the majority of them were due to high-grade serous carcinoma (HGSC). HGSC accounts for 70% of OCs and have a common late-stage diagnosis. Patients usually show initial favorable response to chemotherapy but later on subject to disease relapse and development of acquired resistance.\r\n Understanding the disease biology is important for its early detection and effective treatment. The pathogenesis of HGSC had remained obscure until the identification of its tubal origin. Studies on precursor lesions had gained insights into very early events; however, the carcinogenesis process remained largely underexplored. Meanwhile, molecular subtyping became more important due to the success of targeted therapy using poly(ADP-ribose) polymerase (PARP) inhibitors. However, current clinical trials use different assays and a consensus approach for patient stratification is lacking.\r\n In this thesis, whole genome sequencing (WGS) was used to profile tumor-normal sample pairs from ovarian cancer patients, and a subset of them had samples collected from different anatomical sites. This multi-sample cohort (HIPO59) is suitable for addressing questions about molecular stratification and tumor pathogenesis.\r\n Unifying contemporary DNA-based classifications, more evidences were provided here and consolidated a concept of HGSC dichotomy. Our data suggested that the previously proposed genomic subgroups in HGSC (H-HRD and H-FBI) are characterized by different extent and onset timing of homologous recombination repair (HRR) defect as well as CCNE1 pathway activation. Specifically, HRR deficiency is a common feature and acquired early in H-HRD cases, whereas H-FBI tumors often have CCNE1 pathway activation as an early event. Mechanistic details supporting this observation were revealed by several layers of evidences. Among them, the subgroups also showed differences in surrogate biomarkers for PARP inhibitor response. The HGSC dichotomy reflects meaningful biology of the disease, provides a new perspective of interpreting known biomarkers, and holds the potential for better describing the patient subset that are more likely to benefit from PARP inhibitor treatment.\r\n To get insight into tumor evolution in real-world time, the evolutionary trajectory was computationally reconstructed for each tumor. This highlights an early bifurcation of carcinogenesis pathways in the HGSC dichotomy, despite a common scenario of very early TP53 mutation and an eventual chromosomal instability (CIN) phenotype seen in both subgroups. Furthermore, the reconstructed sample phylogeny trees inform about potential early and late driving events for tumors from all individuals. This can facilitate personalized oncology by providing clinical implications in cascade testing, therapeutic planning and disease monitoring.\r\n Besides, our data raised additional questions worthwhile further investigations. First of all, heredity was found as an influential factor in all histotypes. Contributing factors other than BRCA mutations underlined the link between hereditary DNA repair-deficiency syndromes and ovarian cancer predisposition. Secondly, a variable degree of intra-patient heterogeneity (IPH) was observed in pre-treatment samples of OC and the IPH can potentially stratify patients into distinct prognostic groups. As the method summarizing IPH here supports a wide range of high-throughput profiling platforms, developing a standardized assay suitable for a larger cohort can help evaluate its clinical utility.\r\n Overall, these findings corroborate the concept of HGSC dichotomy by providing mechanistic underpinnings from the aspect of tumor evolution. This integrative viewpoint allows for re-interpreting contemporary knowledge about HGSC, and will help scientists formulate questions about subtype-specific pathogenesis and vulnerabilities. Furthermore, both the dichotomy and IPH status allow for molecular stratification with potential clinical implications. Altogether, the findings in this thesis provide novel opportunities for discovering solid understanding about the biology of HGSC, as well as facilitating personalized oncology in ovarian cancer treatment."^^ . "2021" . . . . . . . "Siao-Han"^^ . "Wong"^^ . "Siao-Han Wong"^^ . . . . . . 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