Hereditary Breast Cancer: BRCA and Other Susceptibility Genes

Female breast cancer is the most common malignancy in most countries. Although a genetic component underlies about 25–30% of cases, mutations in predisposing genes represent the main determinant of the disease only in a minority of affected women (5–10%). The molecular basis of the genetic predisposition is complex and not completely characterised. The susceptibility genes identified to date are classified as high, moderate or low penetrance, according to the extent of cancer risk they confer. Variants associated with breast cancer risk are typically mono-allelic and inherited in an autosomal dominant fashion. Pathogenic variants affecting well-characterised high-penetrance genes, such as BRCA1 and BRCA2, are generally rare but confer a risk higher than fourfold of developing breast cancer. Moreover, in recent years, genome-wide studies have evidenced other putative “actionable” genes, further supporting the clinical relevance of a genetic risk assessment. However, for most moderate- and low-penetrance genes, data on cancer risks are currently limited, and clinical management guidelines are under definition. The identification of individuals with increased genetic risk is a multistep process, carried out in the context of a genetic counselling, which includes a complete evaluation of both personal and family clinical history, the offer of appropriate genetic testing and the interpretation of the molecular analyses. The resulting risk estimates are generally used to guide the access to additional surveillance and other preventative options, including screening (the reader will find in Chap. 13 a discussion on the use of the terms surveillance and screening as referred to early diagnosis of breast cancer) with magnetic resonance imaging and risk-reducing surgery, which should be discussed with a multidisciplinary approach in order to tailor the appropriate prevention strategies to each woman.