ORIGINAL ARTICLE

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

S-M Karppinen¹, R B Barkardottir², K Backenhorn³, T Sydenham⁴, K Syrjäkoski⁵, J Schleutker⁵, T Ikonen⁵, K Pylkäs¹, K Rapakko¹, H Erkko¹, G Johannesdottir², A-M Gerdes⁴, M Thomassen⁴, B A Agnarsson², M Grip⁶, A Kallioniemi⁵, J Kere⁷, L A Aaltonen⁷, A Arason², P Møller⁸, T A Kruse⁴, Å Borg³, R Winqvist¹

¹ Department of Clinical Genetics, Oulu University Hospital, University of Oulu, Oulu, Finland
² Department of Pathology, University Hospital of Iceland, Reykjavik, Iceland
³ Department of Oncology, Lund University Hospital, Lund, Sweden
⁴ Department of Biochemistry, Pharmacology and Genetics, Odense University Hospital, Odense, Denmark
⁵ Laboratory of Cancer Genetics, Institute of Medical Technology, University of Tampere, Tampere University Hospital, Tampere, Finland
⁶ Department of Surgery, Oulu University Hospital, Oulu, Finland
⁷ Department of Medical Genetics, University of Helsinki and Biomedicum Helsinki, Helsinki, Finland
⁸ Department of Cancer Genetics, Norwegian Radium Hospital, Oslo, Norway

Correspondence to:
R Winqvist
Department of Clinical Genetics, Oulu University Hospital, University of Oulu, Oulu, Finland; robert.winqvist{at}oulu.fi

Background: BARD1 was originally identified as a BRCA1-interacting protein but has also been described in tumour-suppressive functions independent of BRCA1. Several studies have indicated that the BARD1 gene is a potential target for germline changes predisposing to breast and ovarian cancer. The C-terminal Cys557Ser change has previously been uncovered to associate with an increased risk of breast cancer and was recently shown to result in defective apoptotic activities.

Aim and methods: Conformation-sensitive gel electrophoresis, minisequencing, TaqMan assays, denaturing high-performance liquid chromatography analysis and DNA sequencing were used to investigate the prevalence of the Cys557Ser allele in a large Nordic case–control study cohort consisting of 2906 patients with breast or ovarian cancer, 734 with prostate cancer, 188 with colorectal cancer, 128 men with breast cancer, and 3591 controls from Finland, Iceland, Denmark, Sweden and Norway.

Results: The frequency of the BARD1 Cys557Ser variant seemed to increase among patients from families with breast or ovarian cancer lacking BRCA1 or BRCA2 mutations: a significant difference was obtained compared with controls (6.8% v 2.7%; p<0.001; odds ratio (OR) 2.6; 95% confidence interval (CI) 1.7 to 4.0) and with patients from BRCA1/BRCA2 mutation-positive families (6.8% v 2.2%; p = 0.01; OR 3.2; 95% CI 1.2 to 8.3). In contrast, no major association with male breast, ovarian, colorectal or prostate cancer was observed. Additionally, a novel BARD1 allele resulting in Ser558Pro was identified in familial breast cancer cases.

Conclusion: These results provide further evidence that BARD1 Cys557Ser confers a slightly increased risk of breast cancer in women.

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