Biochemistry and Pharmacology - Theses
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ItemMolecular and genotypic analysis of BRCA1/2 mutations in ovarian cancer( 2012)The association between germline mutations in the BRCA1 and BRCA2 genes and the development of ovarian cancer has been well established. Identification of families with BRCA mutations provides an opportunity for preventative strategies and cancer risk management in un-affected relatives, to reduce both the morbidity and mortality associated with the disease. Identification of carriers before onset of cancer has historically been the intention of genetic testing, with genetic counselling and genotyping preferentially offered to probands with a strong family history of breast and ovarian cancer. Population-based studies, however, suggest that up to 30% of ovarian cancer patients found to carry a germline BRCA1/2 mutation do not have a significant family history of cancer. The prevalence of mutation carriers amongst women diagnosed with ovarian cancer is unclear, and it is likely that current published population-based estimates of BRCA1/2 mutation prevalence in ovarian cancer cohorts have been confounded due to both selection and testing bias. A population-based investigation into the frequency of germline BRCA1/2 mutations has never been conducted in the Australian population. This study utilises the Australian Ovarian Cancer Study (AOCS) cohort to determine the frequency of germline BRCA1 and BRCA2 mutations in a population-based cohort of epithelial ovarian cancer patients. In Chapter 3, peripheral blood samples obtained from 1001 women diagnosed with invasive non-mucinous ovarian cancer enrolled in the AOCS were screened for point mutations and large deletions in the BRCA1 and BRCA2 genes. Mutations were identified in 14.1% of all diagnoses. This frequency could be considered on the high-end of the range traditionally reported, and leads to the conclusion that offering genetic testing to all women diagnosed with non-mucinous, invasive, epithelial ovarian tumours is a useful approach to increase the number of at-risk families currently identified; members of which can then access appropriate cancer risk management. There is the potential for significant clinical impact of BRCA1/2 germline mutation status on ovarian cancer treatment and management, particularly in the advent of poly (ADP- ribose) polymerase inhibitors and their introduction into clinical trials for BRCA mutation carriers. I explored the survival outcomes and treatment responses, particularly to platin, in BRCA1/2 mutation carriers, compared to women without germline mutations in these genes. My analysis in Chapter 3 revealed that BRCA1/2 germline mutation positive patients retained a sensitivity to platin, even after multiple cycles of treatment. The findings of this aspect of the thesis bring into contention the conventional clinical definition of platin-resistance, with significant implications for routine clinical practice surrounding platin rechallenge in the relapse setting. However, I have also showed increased response rates of mutation carriers to non-platin agents which, together with the impact of mutation status on overall survival, will impact on the development of clinical trials of new regimens and/or novel agents. After further interrogation of the clinical parameters of mutation associated tumours, my data suggests that BRCA1/2 germline mutations appear to occur almost exclusively in high-grade serous ovarian cancers (HGSOC). Sixteen percent of all women diagnosed with a serous ovarian tumour carry a germline mutation in either BRCA1 or BRCA2; this frequency increases to 22.6% of women if I further restrict the cohort to HGSOC. In Chapter 4, further characterisation of HGSOC by high-resolution melt (HRM) analysis and methylation sensitive HRM shows that BRCA-pathway disruption, by somatic mutation of the BRCA1/2 genes or BRCA1 promoter methylation, occurs in an additional 20.5% of serous ovarian tumours. BRCA-pathway disruption is not associated with any of the four molecular subtypes of HGSOC that were first described by this laboratory. My data was utilised in conjunction with that made publically available by The Cancer Genome Atlas (TCGA) study to explore gene expression signatures that may be associated with “BRCA-ness”. A gene expression signature identified in this thesis could identify BRCA1 mutated tumours with a sensitivity of ~80%. The contribution BRCA-pathway disruption, germline as well as somatic, makes to two specific types of chemosensitive response to contemporary platin based treatment regimes is explored further in Chapter 5. The molecular features of a cohort of clinically novel cases that display either extremely prolonged progression-free survival or multiple responses to platin were explored. Disruption of the BRCA-pathway appears to play an important role in patients with multiple responses to platinum-based therapy and to a lesser extent in extremely responsive patients. Novel gene expression analysis also identified several genomic regions that may be involved as potential modifiers of chemosensitivity.