Initiating mutations and chemoprevention in BRCA1 mutation carriers

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. <br><br>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. <br><br>There is also a need to identify an effective, BRCA1-specific chemoprevention strategy as an alternative to risk-reducing surgery.