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Open AccessArticle

BARD1 is a Low/Moderate Breast Cancer Risk Gene: Evidence Based on an Association Study of the Central European p.Q564X Recurrent Mutation

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Department of Molecular Genetics, Institute of Bioorganic Chemistry, Polish Academy of Sciences, 61704 Poznan, Poland
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Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, 71252 Szczecin, Poland
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Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University in Szczecin, 71252 Szczecin, Poland
4
Department of Clinical Genetics and Pathology, University of Zielona Gora, 65046 Zielona Gora, Poland
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Department of Surgery and Oncology, University of Zielona Gora, 65046 Zielona Gora, Poland
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Department of Biology and Medical Genetics, Medical University of Gdansk, 80211 Gdansk, Poland
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Women’s College Research Institute, Women’s College Hospital, Toronto, ON M5S 1B2, Canada
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Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada
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Radiation Oncology Research Unit, Department of Radiation Therapy and Special Oncology, Hannover Medical School, Hannover, 30625 Lower Saxony, Germany
10
Gynaecology Research Unit, Department of Obstetrics and Gynecology, Hannover Medical School, Hannover, 30625 Lower Saxony, Germany
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Present address: Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cancers 2019, 11(6), 740; https://doi.org/10.3390/cancers11060740
Received: 2 May 2019 / Revised: 21 May 2019 / Accepted: 24 May 2019 / Published: 28 May 2019
In addition to several well-established breast cancer (BC) susceptibility genes, the contribution of other candidate genes to BC risk remains mostly undefined. BARD1 is a potentially predisposing BC gene, however, the rarity of its mutations and an insufficient family/study size have hampered corroboration and estimation of the associated cancer risks. To clarify the role of BARD1 mutations in BC predisposition, a comprehensive case-control association study of a recurring nonsense mutation c.1690C>T (p.Q564X) was performed, comprising ~14,000 unselected BC patients and ~5900 controls from Polish and Belarusian populations. For comparisons, two BARD1 variants of unknown significance were also genotyped. We detected the highest number of BARD1 variants in BC cases in any individual BARD1-specific study, including 38 p.Q564X mutations. The p.Q564X was associated with a moderately increased risk of BC (OR = 2.30, p = 0.04). The estimated risk was even higher for triple-negative BC and bilateral BC. As expected, the two tested variants of unknown significance did not show significant associations with BC risk. Our study provides substantial evidence for the association of a deleterious BARD1 mutation with BC as a low/moderate risk allele. The p.Q564X was shown to be a Central European recurrent mutation with potential relevance for future genetic testing. View Full-Text
Keywords: breast cancer; BARD1; genotyping; p.Q564X; p.R658C; p.R659R; breast cancer risk breast cancer; BARD1; genotyping; p.Q564X; p.R658C; p.R659R; breast cancer risk
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Suszynska, M.; Kluzniak, W.; Wokolorczyk, D.; Jakubowska, A.; Huzarski, T.; Gronwald, J.; Debniak, T.; Szwiec, M.; Ratajska, M.; Klonowska, K.; Narod, S.; Bogdanova, N.; Dörk, T.; Lubinski, J.; Cybulski, C.; Kozlowski, P. BARD1 is a Low/Moderate Breast Cancer Risk Gene: Evidence Based on an Association Study of the Central European p.Q564X Recurrent Mutation. Cancers 2019, 11, 740.

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