The BARD1 Cys557Ser variant and breast cancer risk in Iceland

Abstract

Background: Most, if not all, of the cellular functions of the BRCA1 protein are mediated through heterodimeric complexes composed of BRCA1 and a related protein, BARD1. Some breast-cancer-associated BRCA1 missense mutations disrupt the function of the BRCA1/BARD1 complex. It is therefore pertinent to determine whether variants of BARD1 confer susceptibility to breast cancer. Recently, a missense BARD1 variant, Cys557Ser, was reported to be at increased frequencies in breast cancer families. We investigated the role of the BARD1 Cys557Ser variant in a population-based cohort of 1,090 Icelandic patients with invasive breast cancer and 703 controls. We then used a computerized genealogy of the Icelandic population to study the relationships between the Cys557Ser variant and familial clustering of breast cancer.

Methods and findings: The Cys557Ser allele was present at a frequency of 0.028 in patients with invasive breast cancer and 0.016 in controls (odds ratio [OR] = 1.82, 95% confidence interval [CI] 1.11-3.01, p = 0.014). The alleleic frequency was 0.037 in a high-predisposition group of cases defined by having a family history of breast cancer, early onset of breast cancer, or multiple primary breast cancers (OR = 2.41, 95% CI 1.22-4.75, p = 0.015). Carriers of the common Icelandic BRCA2 999del5 mutation were found to have their risk of breast cancer further increased if they also carried the BARD1 variant: the frequency of the BARD1 variant allele was 0.047 (OR = 3.11, 95% CI 1.16-8.40, p = 0.046) in 999del5 carriers with breast cancer. This suggests that the lifetime probability of a BARD1 Cys557Ser/BRCA2 999del5 double carrier developing breast cancer could approach certainty. Cys557Ser carriers, with or without the BRCA2 mutation, had an increased risk of subsequent primary breast tumors after the first breast cancer diagnosis compared to non-carriers. Lobular and medullary breast carcinomas were overrepresented amongst Cys557Ser carriers. We found that an excess of ancestors of contemporary carriers lived in a single county in the southeast of Iceland and that all carriers shared a SNP haplotype, which is suggestive of a founder event. Cys557Ser was found on the same SNP haplotype background in the HapMap Project CEPH sample of Utah residents.

Conclusions: Our findings suggest that BARD1 Cys557Ser is an ancient variant that confers risk of single and multiple primary breast cancers, and this risk extends to carriers of the BRCA2 999del5 mutation.

Figure 1. Proportions of BARD1 Cys557Ser Patients, BRCA2 999del5 Patients, and Reference Groups of Patients Showing Family Histories of Breast Tumors

For each member of the group of Cys557Ser carrier patients ( n = 55), the genealogical database and ICR records of diagnoses were searched to identify all relatives with breast tumors within a distance of three meioses. The proportion of Cys557Ser carriers who had one or more affected relatives, two or more affected relatives, and so on is indicated. For comparison, the analysis was repeated for BRCA2 999del5 patients ( n = 84), non-carriers of both BARD1 and BRCA2 variants ( n = 1,091), all patients who were tested for both variants ( n = 1,209), and all patients in the ICR records ( n = 4,306). Controls were 703 individuals chosen randomly from the genealogical database.

Figure 2. Geographical Ancestry of All Known BARD1 Cys557Ser Carriers

Red bars indicate the locations of ancestors in the fifth generation back for Cys557Ser carriers, and yellow bars represent the average number of ancestors expected for each county based on 1,000 lists of randomly selected age- and sex-matched controls. One county in the east, S-Múlasýsla (shaded in blue), shows an excess of BARD1 Cys557Ser ancestors that retained significance after Bonferroni correction. Two counties (shaded in pink) exhibited a marginally significant deficit of BARD1 Cys557Ser ancestors, which did not survive Bonferroni correction.