Common genetic variation at BARD1 is not associated with breast cancer risk in BRCA1 or BRCA2 mutation carriers

QueenslanInstitute for Medical Research, Brisbane, Australia.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 03/2011; 20(5):1032-8. DOI: 10.1158/1055-9965.EPI-10-0909
Source: PubMed


Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies.
A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated.
The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71-1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59-1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk.
Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers.
Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk.

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Available from: Gail E Tomlinson, Oct 05, 2015
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    • "Recently, G1743C (Cys557Ser) has been reported for no association with the predisposition of familial breast cancer in an Australian population based case control study [39]. In a cohort based study of a French population, nine common SNPs of BARD1 including G1743C (Cys557Ser) were not shown any role as modifier of risk in BRCA1/2 mutant carriers [40]. Furthermore, BARD1 SNPs rs6435862 and rs3768716 and some known common SNPs has been found significantly associated with the aggressive neuroblastoma [41].During the last decade, approximately 12 nsSNPs have been studied in different populations for their association with the predisposition to various female cancers. "
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    ABSTRACT: Background The BARD1 gene encodes for the BRCA1-associated RING domain (BARD1) protein. Germ line and somatic mutations in BARD1 are found in sporadic breast, ovarian and uterine cancers. There is a plethora of single nucleotide polymorphisms (SNPs) which may or may not be involved in the onset of female cancers. Hence, before planning a larger population study, it is advisable to sort out the possible functional SNPs. To accomplish this goal, data available in the dbSNP database and different computer programs can be used. To the best of our knowledge, until now there has been no such study on record for the BARD1 gene. Therefore, this study was undertaken to find the functional nsSNPs in BARD1. Result 2.85% of all SNPs in the dbSNP database were present in the coding regions. SIFT predicted 11 out of 50 nsSNPs as not tolerable and PolyPhen assessed 27 out of 50 nsSNPs as damaging. FastSNP revealed that the rs58253676 SNP in the 3′ UTR may have splicing regulator and enhancer functions. In the 5′ UTR, rs17489363 and rs17426219 may alter the transcriptional binding site. The intronic region SNP rs67822872 may have a medium-high risk level. The protein structures 1JM7, 3C5R and 2NTE were predicted by PDBSum and shared 100% similarity with the BARD1 amino acid sequence. Among the predicted nsSNPs, rs4986841, rs111367604, rs13389423 and rs139785364 were identified as deleterious and damaging by the SIFT and PolyPhen programs. Additionally, I-Mutant showed a decrease in stability for these nsSNPs upon mutation. Finally, the ExPASy-PROSIT program revealed that the predicted deleterious mutations are contained in the ankyrin ring and BRCT domains. Conclusion Using the available bioinformatics tools and the data present in the dbSNP database, the four nsSNPs, rs4986841, rs111367604, rs13389423 and rs139785364, were identified as deleterious, reducing the protein stability of BARD1. Hence, these SNPs can be used for the larger population-based studies of female cancers.
    PLoS ONE 10/2012; 7(10). DOI:10.1371/journal.pone.0043939 · 3.23 Impact Factor
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    ABSTRACT: Inherited BRCA1 mutations confer elevated cancer risk. Recent studies have identified genes that encode proteins that interact with BRCA1 as modifiers of BRCA1-associated breast cancer. We evaluated a comprehensive set of genes that encode most known BRCA1 interactors to evaluate the role of these genes as modifiers of cancer risk. A cohort of 2,825 BRCA1 mutation carriers was used to evaluate the association of haplotypes at ATM, BRCC36, BRCC45 (BRE), BRIP1 (BACH1/FANCJ), CTIP, ABRA1 (FAM175A), MERIT40, MRE11A, NBS1, PALB2 (FANCN), RAD50, RAD51, RAP80, and TOPBP1, and was associated with time to breast and ovarian cancer diagnosis. Statistically significant false discovery rate (FDR) adjusted P values for overall association of haplotypes (P(FDR)) with breast cancer were identified at ATM (P(FDR) = 0.029), BRCC45 (P(FDR) = 0.019), BRIP1 (P(FDR) = 0.008), CTIP (P(FDR) = 0.017), MERIT40 (P(FDR) = 0.019), NBS1 (P(FDR) = 0.003), RAD50 (P(FDR) = 0.014), and TOPBP1 (P(FDR) = 0.011). Haplotypes at ABRA1 (P(FDR) = 0.007), BRCC45 (P(FDR) = 0.016 and P(FDR) = 0.005 in two haplotype blocks), and RAP80 (P(FDR) < 0.001) were associated with ovarian cancer risk. Overall, the data suggest that genomic variation at multiple loci that encode proteins that interact biologically with BRCA1 are associated with modified breast cancer and ovarian cancer risk in women who carry BRCA1 mutations.
    Cancer Research 07/2011; 71(17):5792-805. DOI:10.1158/0008-5472.CAN-11-0773 · 9.33 Impact Factor
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    ABSTRACT: The BRCA1-associated RING domain (BARD1) gene has been identified as a high-penetrance gene for breast cancer, whose germline and somatic mutations were reported in both non-BRCA1/2 hereditary site-specific and sporadic breast cancer cases. Some association studies suggested that the BRAD1 Cys557Ser variant might be associated with increased risk of breast cancer, but the results remain conflicting rather than conclusive. In order to derive a more precise estimation of the relationship, this meta-analysis was performed. Eligible studies were identified by searching several databases for relevant reports published before March 2011. In total, 14 studies (11,870 cases and 7,687 controls) were included in the present meta-analysis. The pooled odds ratio (OR) with 95% confidence interval (CI) for breast cancer risk associated with Cys557Ser carrier was estimated. The carrier frequency of the Cys557Ser mutation was 3.85% (457/11,870) in patients with breast cancer and 3.29% (253/7,687) in healthy controls. When all studies were pooled into the meta-analysis, there was no evidence for significant association between Cys557Ser mutation and breast cancer risk (OR 1.14, 95% CI 0.94-1.34). In the subgroup analyses by design of experiment and family history with BRCA1/2 status (unselected cases, family history with non-BRCA1/2 cases, and family history with BRCA1/2-positive cases), no significant associations were found in any subgroup of population. This meta-analysis strongly suggests that BARD1 Cys557Ser mutation is not associated with increased breast cancer risk.
    Journal of Cancer Research and Clinical Oncology 08/2011; 137(10):1463-8. DOI:10.1007/s00432-011-1006-0 · 3.08 Impact Factor
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