AbstractBRCA1 mutation carriers have a significant lifetime risk of developing breast cancer. Currently, these women are offered risk-reducing bilateral mastectomies, which have significant physical risks and psychosexual implications, or chemoprevention strategies that have little evidence to support their efficacy in this cohort.
There is a clinical need to establish whether BRCA1 deficient women acquire a significant mutational burden prior to cancer formation, as development of a temporal biomarker would help stratify risk, and thus aid in decision making regarding timing of risk-reducing surgery. This thesis examines the initiating mutations in BRCA1 mutation carriers via two complementary approaches: a retrospective study of breast tissue utilising immunohistochemistry and FISH analysis of mutations known to be implicated in BRCA1-related tumourogenesis; and a prospective study of 'normal' BRCA1 mutation carrier breast tissue using next generation sequencing to identify somatic mutations. Neither approach identified a significant mutational burden in non-cancer breast tissue in BRCA1 mutation carriers.
There is also a need to identify an effective, BRCA1-specific chemoprevention strategy as an alternative to risk-reducing surgery. Previous work in our lab has demonstrated that oestrogen and its metabolites mediate DNA damage in breast cell lines and this damage is exacerbated by BRCA1 deficiency. The results of a proof-of-concept clinical trial using suppression of oestrogen levels in BRCA1-mutation carriers are presented, ultimately highlighting recruitment as the primary obstacle to development of BRCA1-specific chemoprevention strategies.
|Date of Award||Dec 2020|
|Supervisor||Kienan Savage (Supervisor), Denis Harkin (Supervisor) & Stuart McIntosh (Supervisor)|