The biological effects and clinical implications of BRCA mutations: where do we go from here?

Abstract

BRCA1 and BRCA2 are tumour-suppressor genes encoding proteins that are essential for the repair of DNA double-strand breaks by homologous recombination (HR). Cells that lack either BRCA1 or BRCA2 repair these lesions by alternative, more error-prone mechanisms. Individuals carrying germline pathogenic mutations in BRCA1 or BRCA2 are at highly elevated risk of developing breast and/or ovarian cancer. Genetic testing for germline pathogenic mutations in BRCA1 and BRCA2 has proved to be a valuable tool for determining eligibility for cancer screening and prevention programmes. In view of increasing evidence that the HR DNA repair pathway can also be disrupted by sequence variants in other genes, screening for other BRCA-like defects has potential implications for patient care. Additionally, there is a growing argument for directly testing tumours for pathogenic mutations in BRCA1, BRCA2 and other genes involved in HR-DNA repair as inactivation of these genes may be strictly somatic. Tumours in which HR-DNA repair is altered are most likely to respond to emerging targeted therapies, such as inhibitors of poly-ADP ribose polymerase. This review highlights the biological role of pathogenic BRCA mutations and other associated defects in DNA damage repair mechanisms in breast and ovarian cancer, with particular focus on implications for patient management strategies.

Figure 1

Role of BRCA2 in DNA DSB repair by HR. Diagram courtesy of Gaël Millot, Curie Institute and University Pierre and Marie Curie, Paris, France.^,

Figure 2

High-grade ovarian carcinoma: frequency of BRCA1/2 inactivation in and impact on survival; frequency of alterations of genes involved in DNA damage sensors or HR (and not repair), including BRCA1 and BRCA2. Reprinted by permission from Macmillan Publishers Ltd, copyright 2011.

Figure 3

Proteins involved in DNA DSB repair by HR. RPA, replication protein A. Figure adapted from Sy et al. and Skorski. Reprinted by permission from Macmillan Publishers Ltd, copyright 2002, and from PNAS.

Figure 4

Olaparib maintenance therapy in platinum-sensitive relapsed ovarian cancer: progression-free survival in patients harbouring a pathogenic BRCA mutation. Reprinted from Ledermann et al., copyright 2014, with permission from Elsevier.