Abstract
Purpose
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.
Methods
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.
Results
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.
Conclusions
This meta-analysis strongly suggests that BARD1 Cys557Ser mutation is not associated with increased breast cancer risk.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Brzovic PS, Meza JE, King MC, Klevit RE (2001) BRCA1 RING domain cancer-predisposing mutations. Structural consequences and effects on protein–protein interactions. J Biol Chem 276:41399–41406
CHEK2 Breast Cancer Consortium (2002) Low-penetrance susceptibility to breast cancer due to CHEK2*1100delC in noncarriers of BRCA1 or BRCA2 mutations. Nat Genet 31:55–59
Cybulski C, Górski B, Huzarski T et al (2004) CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 75:1131–1135
Dechend R, Hirano F, Lehmann K et al (1999) The Bcl-3 oncoprotein acts as a bridging factor between NF-kappaB/Rel and nuclear co-regulators. Oncogene 18:3316–3323
DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clini Trials 7:177–188
Easton DF (1999) How many more breast cancer predisposition genes are there? Breast Cancer Res 1:14–17
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634
Ghimenti C, Sensi E, Presciuttini S et al (2002) Germline mutations of the BRCA1-associated ring domain (BARD1) gene in breast and breast/ovarian families negative for BRCA1 and BRCA2 alterations. Genes Chromosomes Cancer 33:235–242
Gorringe KL, Choong DY, Visvader JE, Lindeman GJ, Campbell IG (2008) BARD1 variants are not associated with breast cancer risk in Australian familial breast cancer. Breast Cancer Res Treat 111(3):505–509
Goss PE, Sierra S (1998) Current perspectives on radiation-induced breast cancer. J Clin Oncol 16(1):338–347
Guénard F, Labrie Y, Ouellette G, Beauparlant CJ, Durocher F, INHERIT BRCAs (2009) Genetic sequence variations of BRCA1-interacting genes AURKA, BAP1, BARD1 and DHX9 in French Canadian families with high risk of breast cancer. J Hum Genet 54(3):152–161
Hashizume R, Fukuda M, Maeda I et al (2001) The RING heterodimer BRCA1-BARD1 is a ubiquitin ligase inactivated by a breast cancer-derived mutation. J Biol Chem 276:14537–14540
Irminger-Finger I, Jefford CE (2006) Is there more to BARD1 than BRCA1? Nat Rev Cancer 6:382–391
Ishitobi M, Miyoshi Y, Hasegawa S et al (2003) Mutational analysis of BARD1 in familial breast cancer patients in Japan. Cancer Lett 200:1–7
Jakubowska A, Cybulski C, Szymańska A et al (2008) BARD1 and breast cancer in Poland. Breast Cancer Res Treat 107(1):119–122
Jefford CE, Feki A, Harb J, Krause KH, Irminger-Finger I (2004) Nuclear–cytoplasmic translocation of BARD1 is linked to its apoptotic activity. Oncogene 23:3509–3520
Johnatty SE, Beesley J, Chen X et al (2009) The BARD1 Cys557Ser polymorphism and breast cancer risk: an Australian case–control and family analysis. Breast Cancer Res Treat 115(1):145–150
Karppinen SM, Heikkinen K, Rapakko K, Winqvist R (2004) Mutation screening of the BARD1 gene: evidence for involvement of the Cys557Ser allele in hereditary susceptibility to breast cancer. J Med Genet 41(9):e114
Karppinen SM, Barkardottir RB, Backenhorn K et al (2006) Nordic collaborative study of the BARD1 Cys557Ser allele in 3956 patients with cancer: enrichment in familial BRCA1/BRCA2 mutation-negative breast cancer but not in other malignancies. J Med Genet 43(11):856–862
Mantel N, Haenszel W (1959) Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719–748
Martin A-M, Weber BL (2000) Genetic and hormonal risk factors in breast cancer. J Natl Cancer Inst (Bethesda) 92(14):1126–1135
Miki Y, Swensen J, Shattuck-Eidens D et al (1994) A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266:66–71
Onay VU, Briollais L, Knight JA et al (2006) SNP–SNP interactions in breast cancer susceptibility. BMC Cancer 6:114
Ratajska M, Antoszewska E, Piskorz A et al (2011) Cancer predisposing BARD1 mutations in breast-ovarian cancer families. Breast Cancer Res Treat (Epub ahead of print)
Sauer MK, Andrulis IL (2005) Identification and characterization of missense alterations in the BRCA1 associated RING domain (BARD1) gene in breast and ovarian cancer. J Med Genet 42:633–638
Spurdle M, Marquart L, McGuffog L et al (2011) Common genetic variation at BARD1 is not associated with Breast cancer risk in BRCA1 or BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev 20:1032–1038
Stacey SN, Sulem P, Johannsson OT et al (2006) The BARD1 Cys557Ser variant and breast cancer risk in Iceland. PLoS Med 3(7):e217
Swift M, Reitnauer PJ, Morrell D, Chase CL (1987) Breast and other cancers in families with ataxia-telangiectasia. N Engl J Med 316:1289–1294
Tarasov VA, Aslanyan MM, Tsyrendorzhiyeva ES et al (2006) Genetically determined subdivision of human populations with respect to the risk of breast cancer in women. Dokl Biol Sci 406:66–69
Thai TH, Du F, Tsan JT et al (1998) Mutations in the BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine cancers. Hum Mol Genet 7:195–202
Vahteristo P, Syrjäkoski K, Heikkinen T et al (2006) BARD1 variants Cys557Ser and Val507Met in breast cancer predisposition. Eur J Hum Genet 14(2):167–172
Wooster R, Bignell G, Lancaster J et al (1995) Identification of the breast cancer susceptibility gene BRCA2. Nature 378:789–792
Wu LC, Wang ZW, Tsan JT et al (1996) Identification of a RING protein that can interact in vivo with the BRCA1 gene product. Nat Genet 14:430–440
Conflict of interest
We declare that we have no conflict of interest.
Author information
Authors and Affiliations
Corresponding authors
Additional information
Da-Peng Ding and Ying Zhang contributed equally to this work and should be considered as co-first authors.
Rights and permissions
About this article
Cite this article
Ding, DP., Zhang, Y., Ma, WL. et al. Lack of association between BARD1 Cys557Ser variant and breast cancer risk: a meta-analysis of 11,870 cases and 7,687 controls. J Cancer Res Clin Oncol 137, 1463–1468 (2011). https://doi.org/10.1007/s00432-011-1006-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00432-011-1006-0