Ovarian cancer is regarded as the most lethal gynecological malignancy around the world. Despite the advancing medical improvements in both surgery and chemotherapy, the mortality rate did not appear to be reduced. This could be account for the late diagnosis of ovarian cancer until advanced stage. Recently, p-21 activated kinase 4 (PAK4), as a potential significant prognostic marker of ovarian cancer, has been widely studied on its contribution in oncogenesis properties. It was suggested that PAK4 proteins were activated and confer chemoresistance in ovarian cancers. In this study, we hypothesized that the up-regulation of PAK4 in ovarian cancers maybe resulted from mutations and amplification in genomic DNA level. Investigations on PAK4 genetic alterations were carried out. Recurrent mutations were found in the kinase domain of PAK4 in three ovarian cancer cell lines and two clinical samples. Single mutation was found in the exon 3 of PAK4 coding for GTPase binding domain (GTB). Amplifications of PAK4 genomic DNA were also found in four ovarian cancer cell lines. On top of that, dysregulated PAK4 level in chemosensitivity ovarian cancer cell line, A2780s showed PAK4 contribution in protection against apoptosis. Meanwhile PAK4 transfected chemoresistance cell line A2780cp also showed similar effect to PAK4 transfected A2780s. Kinase-dead and constitutively active PAK4 did not show any significance contribution to the apoptosis property. This may suggest that PAK4 do not operate all kinase domains towards apoptotic function. Immortalized normal ovarian epithelial cell line, HOSE6-3 was also upregulated with PAK4 transfection. However it did not induce the oncogenesis property of cell survival. / published_or_final_version / Pathology / Master / Master of Medical Sciences

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

University of Macau / Institute of Chinese Medical Sciences

Ovarian cancer is the fifth most common cause of cancer death in females and the most lethal gynecologic cancer. Globally, an estimated 240,000 people are diagnosed with ovarian cancer each year, with 22,530 new cases in the United States in 2019. Parity, oral contraceptive use, and lactation are protective, while early menarche, late menopause, and nulliparity have opposite effects. The “incessant ovulation” theory has thus emerged, in which a higher number of ovulations may be a cause of epithelial ovarian cancer (EOC). However, the mechanisms of this theory are unknown; one possibility is that the chance of acquiring a cancer-initiating pathogenic variant increases with each ovulatory cycle because of a microenvironment that promotes DNA damage. In this dissertation, we aimed to leverage genetic epidemiologic data to test this potential mechanism by evaluating the presence of gene-environment interaction between DNA repair capacity (measured through the presence of pathogenic variants in DNA repair genes) and lifetime ovulatory years (LOY). In the first aim of this dissertation, we conducted a systematic review and meta-analysis, following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, to formally evaluate the strength of evidence and to generate summary point estimates for the association between LOY and EOC. We then executed two analytic aims to evaluate if the presence of pathogenic variants in DNA repair genes exacerbated the increase in ovarian cancer risk associated with LOY. In Aim 2, we evaluated interaction on the additive scale in the United Kingdom (UK) Biobank through use of a novel DNA repair capacity score developed in this dissertation, measured by quantifying the number of pathogenic variants present per individual from a list of 163 DNA repair genes, using whole exome sequencing (WES) data. In Aim 3, we evaluated the presence of interaction between pathogenic BRCA1/2 status and LOY in the Breast Cancer Family Registry (BCFR), a cohort enriched for familial risk. In both empirical aims, we assessed the presence of interaction on the additive scale using the relative excess risk due to interaction (RERI) formula. We compared results across the two empirical aims. We found the relationship between lifetime ovulations and ovarian cancer risk to be consistent and replicable in the published literature. In pooled estimates from 22 published studies, a one-year increase in LOYs was associated with a 4% (3-6%) increased risk of ovarian cancer and those with a high number of ovulations (compared to low LOYs) had a 2.15-fold (95% CI 1.82, 2.54) increased risk of ovarian cancer. We also confirmed the positive association between increasing LOYs and ovarian cancer risk in the UK Biobank and the BCFR cohorts. Although interaction on the additive scale was not detected, there were strong positive associations between pathogenic variants in DNA repair genes and ovarian cancer risk. In the UK Biobank, the presence of at least one pathogenic variant in a DNA repair gene was associated with a significant 27% increased risk of epithelial ovarian cancer (EOC) (95% CI 5-55%). Among women at high risk of ovarian cancer due to family history of breast and/or ovarian cancer, there was a strong relationship between BRCA1/2 pathogenic variants and ovarian cancer, regardless of the number of ovulations experienced. The association between LOY and ovarian cancer was found to be consistent and replicable, despite differences in study design, covariates, and measurement. We also detected robust evidence that increasing lifetime ovulations and pathogenic DNA repair variants were associated with ovarian cancer risk. Such variants were exceedingly rare in both cohorts, which limited power to detect interaction in an already rare cancer. Despite such associations, there was no evidence of synergy between LOY and impaired DNA repair capacity, but rather, high LOY and impaired DNA repair capacity may be independent risk factors of ovarian cancer. Each exposure may describe a separate class of women at increased risk of ovarian cancer that should be targeted for future prevention and screening strategies.

published_or_final_version / abstract / Pathology / Master / Master of Philosophy

No description available.

Thesis (M.A.)--York University, 2005. Graduate Programme in Kinesiology and Health Science. / Typescript. Includes bibliographical references (leaves 89-92). Also available on the Internet. MODE OF ACCESS via web browser by entering the following URL: http://gateway.proquest.com/openurl?url%5Fver=Z39.88-2004&res%5Fdat=xri:pqdiss &rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&rft_dat=xri:pqdiss:MR11878

High-grade serous ovarian carcinoma (HGSOC) is characterised by genomic instability, ubiquitous TP53 loss, widespread disease at diagnosis and the frequent emergence of platinum resistance. This thesis explores the use of high-throughput genomics technologies to understand if resistance could be explained by the model of tumour evolution. We performed SNP array analysis of a cell line model system of platinum resistance consisting of matched cell lines from three cases of HGSOC established before and after clinical resistance developed, the OVOl clinical study consisting of six matched pairs of tumours before and after three cycles of chemotherapy, and the OV03/0V04 study consisting of 18 cases sampled at multiple timepoints and from multiple metastatic sites. The results showed evidence of metastatic site dependent divergence. Moreover, mutually exclusive loss of heterozygosity patterns between presentation and relapse genomes, including all the cases in the cell line system and one of two OV03 cases for which relapse material was available, suggest that the relapse arises from a minor subclone of the presentation disease, while in the remaining case, the subclone with an NFJ homozygous deletion was enriched in the relapsed disease. I then asked which mutational process drives evolution. Using next-generation sequencing (NGS), I compared the structural variants between and within cases in the model system and in 6 cases of the OV03 cohort. From the genomic signatures in the cell lines, I demonstrated that a case with homologous recombination (HR) deficiency acquired numerous translocations and small deletions (median size of 13.4kb) , whereas another showed a novel tandem duplicator phenotype (median size of tandem duplications was 350kb). Mutator phenotypes in both cases arose early in progression and persisted, but the tumour with HR deficiency showed evidence of re-stabilising its ,"genome and lost platinum sensitivity after a revertant BRCA2 mutation restored its HR function. A subset of tumours from the Cancer Genome Atlas (TCGA) dataset suggested that these two phenotypes were mutually exclusive. Amongst the six OV03 cases, preliminary analysis suggests that one case showed an amplifier phenotype and three cases showed evidence of parallel evolution. Taken together, early onset of mutator phenotypes and parallel evolution may provide a mechanism by which resistance evolves. Further work should aim to identify the processes involved in tumour evolution in 'purified' populations such as cancer stem cells.

published_or_final_version / abstract / Clinical Oncology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy