Introduction

Approximately 5% of breast cancers and up to 10% of epithelial ovarian cancers may be attributed to mutations (errors) in high-risk susceptibility genes. These genes include BRCA1 and BRCA2, which are mutated in about 15% of site-specific breast cancer families and in up to 80% of families with multiple cases of both ovarian and breast cancer. The importance of BRCA1 and BRCA2 genes stems from the fact that they are ‘caretaker’ cancer-susceptibility genes, which encode molecules that act as sensors of DNA defects and participate in the repair process. Deficiencies in such caretaker genes permit other genetic defects to accumulate and this ultimately results in genetic instability.

The BRCA1 and BRCA2 tumour suppressor genes

The BRCA1 gene locus was first identified by Hall and colleagues at University of California, Berkeley, in 1990 and was subsequently cloned in 1994 (Figure 5.1). At the same time in 1994, the BRCA2 gene was discovered by Stratton and Wooster at The Institute of Cancer Research, UK. The identification of BRCA1 and BRCA2 were significant milestones in the management of families with breast and ovarian cancers, facilitating the subsequent incorporation of these genes into familial risk assessment, genetic counselling and mutational analysis.

The BRCA1 gene, located on chromosome 17q21, encodes a large, predominantly nuclear 1863 amino acid protein with an estimated molecular weight of 220 kDa. It consists of multiple functional domains, including an N-terminal RING, two nuclear localisation signals and two C-terminal BRCT domains of approximately 110 residues.