Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.706986
Title: BRCAness in breast cancer
Author: Irwin, Gareth William
ISNI:       0000 0001 2445 5382
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2016
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Abstract:
Background - Breast cancer can be defined various techniques such as immunohistochemistry, gene expression profiles and the presence of genetic mutations. One of these subgroups possesses a sensitivity to DNA-damaging chemotherapy, the BRCAness phenotype. It remains difficult to define this subgroup prior to treatment. This project aims to define BRCAness in breast cancer by assessing BRCAness using three methods: microarray profiling, immunohistochemistry and genetic mutations. Results - A 44 gene signature to predict DNA Damage Repair Deficient Breast cancers was developed from a training cohort of FFPE derived breast tumours enriched for BRCA1/2 mutant cancers. This signature was retrospectively applied to a cohort of sporadic breast cancers and subsequently validated as predictive for improved outcome in a cohort of early-stage breast cancers treated with anthracycline-based chemotherapy, a group that exhibits BRCAness. BRCA1 expression was measured by immunohistochemistry, however, this approach failed to predict benefit from chemotherapy in this study. Finally, a mutation, identified in SF3B1, plays a significant role in the DNA damage response and that absence or mutation of SF3B1 leads to sensitivity to DNA damage and this may be a predictor of BRCAness. Conclusion - In summary, we have shown that BRCAness is best defined by gene array profiling. We have shown that BRCA1 immunohistochemistry is of limited use for predicting patient outcomes in breast cancer. Finally, we identified of specific mutations within SF3B1 that induce sensitivity to DNA damage based chemotherapy.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.706986  DOI: Not available
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