BARD1 is a Low/Moderate Breast Cancer Risk Gene: Evidence Based on an Association Study of the Central European p.Q564X Recurrent Mutation
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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DOI：
10.3390/cancers11060740
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发表时间：
2019-05
期刊：
影响因子：
5.2
通讯作者：
M. Suszyńska;W. Kluźniak;D. Wokołorczyk;A. Jakubowska;T. Huzarski;J. Gronwald;T. Dębniak;M. Szwiec;M. Ratajska;K. Klonowska;S. Narod;N. Bogdanova;T. Dörk;J. Lubiński;C. Cybulski;P. Kozłowski
中科院分区：
文献类型：
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作者：
M. Suszyńska;W. Kluźniak;D. Wokołorczyk;A. Jakubowska;T. Huzarski;J. Gronwald;T. Dębniak;M. Szwiec;M. Ratajska;K. Klonowska;S. Narod;N. Bogdanova;T. Dörk;J. Lubiński;C. Cybulski;P. Kozłowski
除了一些确定的乳腺癌易感基因外，其他候选基因对乳腺癌风险的贡献仍未确定。BARD1是一种潜在的易患BC的基因，然而，其突变的罕见性和不足的家族/研究规模阻碍了相关癌症风险的证实和估计。为了阐明BARD1突变在BC易感中的作用，对反复出现的无义突变c.1690C >t （p.Q564X）进行了一项全面的病例-对照关联研究，其中包括来自波兰和白俄罗斯人群的约14,000名未选择的BC患者和约5900名对照。为了进行比较，我们还对两个意义未知的BARD1变异进行了基因分型。在任何BARD1特异性研究中，我们在BC病例中检测到最多的BARD1变异，包括38个p.Q564X突变。p. q564x与BC风险增加相关（OR = 2.30, p = 0.04）。三阴性BC和双侧BC的估计风险甚至更高。正如预期的那样，两种未知意义的测试变体没有显示出与BC风险的显著关联。我们的研究为有害的BARD1突变与BC作为低/中度风险等位基因的关联提供了大量证据。p.Q564X被证明是中欧复发性突变，与未来的基因检测有潜在的相关性。
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.