The contribution of BRCA1 and BRCA2 to ovarian cancer

Abstract

Germline mutations of the BRCA1 and BRCA2 genes confer a high life-time risk of ovarian cancer. They represent the most significant and well characterised genetic risk factors so far identified for the disease. The frequency with which BRCA1/2 mutations occur in families containing multiple cases of ovarian cancer or breast and ovarian cancer, and in population-based ovarian cancer series varies geographically and between different ethnic groups. There are differences in the frequency of common mutations and in the presence of specific founder mutations in different populations. BRCA1 and BRCA2 are responsible for half of all families containing two or more ovarian cancer cases. In population-based studies, BRCA1 and BRCA2 mutations are present in 5-15% of all ovarian cancer cases. Often, individuals in which mutations are identified in unselected cases have no family history of either ovarian or breast cancer. The ability to identify BRCA1/2 mutations has been one of the few major success stories over the last few years in the clinical management of ovarian cancer. Currently, unaffected individuals can be screened for mutations if they have a family history of the disease. If a mutation is identified in the family, and if an individual is found be a mutation carrier, they can be offered clinical intervention strategies that can dramatically reduce their ovarian cancer risks. In some populations with frequent founder mutations screening may not be dependent on whether a mutation is identified in an affected relative.

Figure 1

Pie charts showing the proportion of families with BRCA1 (blue), BRCA2 (red) and no detectable mutation (yellow) in UK and USA familial ovarian cancer registries divided by type and extent of family history. (a) Higher proportion of families with mutations with increasing number of ovarian cancer cases i) 2 ovarian cancer cases only, ii) 3 or more ovarian cancer cases only. (b) Higher proportion of families with mutations with increasing number of breast cancer cases i) 2 or more ovary and no breast cancer, ii) 2 or more ovary and one breast cancer case, iii) 2 or more ovary and 2 or more breast cancer cases.

Figure 2

Proportion of breast and ovarian cancer cases in families with mutations in the 5′, central and 3′ regions of each gene. Yellow indicates the exon structure of each gene and in the pie charts, dark blue are breast cancer cases and light blue are ovarian cancer cases. Data from Thompson et al. (2001, 2002a) and Ramus et al. (2007) (excluding overlapping families). (a) BRCA1; the ratio of breast to ovarian cancer in each region is 1.4, 0.9 and 2.2 respectively showing increased risk of ovarian cancer for mutations in the central region bounded by 2388–4185bp. (b) BRCA2; the ratio of breast to ovarian cancer in each region is 10.3, 2.0 and 6.2 respectively showing an even more pronounced increased risk of ovarian cancer (or decreased risk of breast cancer) for mutations in the central OCCR, bounded by 3059–6629bp.

Figure 3

Map of the world showing the proportion of detected BRCA1 and BRCA2 mutations that are unique or identified multiple times within a study. The red and yellow pie charts indicate family based studies where red represents common mutations and yellow represents unique mutations. The blue pie charts represent population‐based studies where dark blue are common mutations and light blue are unique mutations. Studies included are those from Tables 1 and 3 that performed full screening of both genes, have greater than 10 mutations and have listed the mutations identified. Three studies with partial screening were also included (from Pakistan, Turkey and Finland). Some populations have a high proportion of common mutations ie. Poland and Sweden, while others have a high proportion of unique mutations ie. Pakistan, Turkey and USA.