A recessive variant of XRCC4 predisposes to non- BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization.
A recessive variant of XRCC4 predisposes to non- BRCA1/2 breast cancer in chinese women and impairs the DNA damage response via dysregulated nuclear localization.
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XRCC4 的隐性变异使中国女性易患非 BRCA1/2 乳腺癌，并通过核定位失调损害 DNA 损伤反应
DOI：
10.18632/oncotarget.2623
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发表时间：
2014-12-15
期刊：
影响因子：
--
通讯作者：
Shao ZM
中科院分区：
文献类型：
--
作者：
He M;Hu X;Chen L;Cao AY;Yu KD;Shi TY;Kuang XY;Shi WB;Ling H;Li S;Qiao F;Yao L;Wei Q;Di GH;Shao ZM
XRCC 4在维持基因组稳定性的非同源末端连接途径中起关键作用。在这项两阶段病例对照研究中，1，764名非BRCA 1/2乳腺癌患者和1，623名无癌症对照，我们调查了XRCC 4遗传变异对中国女性乳腺癌易感性的贡献。我们鉴定了XRCC 4的一种隐性错义变异rs3734091（c.739G>T，p.Ala247Ser），它与乳腺癌风险增加显著相关（比值比[OR] = 3.92，P = 0.007），特别是与发展为三阴性乳腺癌的风险显著相关（OR = 18.65，P < 0.0001）。这种p.Ala247Ser变异体在细胞和组织水平上干扰了XRCC 4在rs3734091-T等位基因纯合细胞中的核定位，但在杂合细胞中不干扰。在杂合细胞中，野生型XRCC 4促进了XRCC 4A 247 S突变体的核定位，从而补偿了XRCC 4A 247 S受损的定位。这提供了一种生物学机制，rs3734091仅在隐性模型下赋予非BRCA 1/2乳腺癌易感性增加。进一步的功能分析表明，p.Ala247Ser削弱了DNA损伤修复能力，并最终扰乱了基因组的稳定性。总之，我们的研究结果证明了XRCC 4在非BRCA 1/2乳腺癌易感性中的作用，并揭示了其潜在的生物学作用机制。
XRCC4 plays a crucial role in the non-homologous end joining pathway that maintains genome stability. In this two-stage case-control study with 1,764 non-BRCA1/2 breast cancer patients and 1,623 cancer-free controls, we investigated the contribution of genetic variants of XRCC4 to breast cancer susceptibility in Chinese women. We identified a recessive missense variant, rs3734091 (c.739G>T, p.Ala247Ser), of XRCC4 that was significantly associated with an increased risk of breast cancer (odds ratio [OR] = 3.92, P = 0.007), particularly with the risk of developing triple-negative breast cancer (OR = 18.65, P < 0.0001). This p.Ala247Ser variant disturbed the nuclear localization of XRCC4 in cells homozygous for the rs3734091-T allele but not in heterozygous cells at both the cellular and tissue levels. In heterozygous cells, wild-type XRCC4 facilitated the nuclear localization of the XRCC4A247S mutant, thus compensating for the impaired localization of XRCC4A247S. This provided a biological mechanism by which rs3734091 conferred an increased susceptibility to non-BRCA1/2 breast cancer exclusively under a recessive model. Further functional analyses revealed that p.Ala247Ser impaired the DNA damage repair capacity and ultimately perturbed genomic stability. Taken together, our findings document the role of XRCC4 in non-BRCA1/2 breast cancer predisposition and reveal its underlying biological mechanism of action.
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DOI：
10.1016/s0921-8777(98)00063-9
发表时间：
1999-01-26
期刊：
MUTATION RESEARCH-DNA REPAIR
影响因子：
--
作者：
Bryans, M;Valenzano, MC;Stamato, TD
通讯作者：
Stamato, TD
影响因子：
5.3
作者：
He, Jing;Qiu, Li-Xin;Li, Jin
通讯作者：
Li, Jin
影响因子：
3.8
作者：
Lee, KJ;Jovanovic, M;Dynan, WS
通讯作者：
Dynan, WS
影响因子：
1.9
作者：
Cifci, S.;Yilmaz, M.;Pehlivan, S.
通讯作者：
Pehlivan, S.
影响因子：
0.9
作者：
Davis AJ;Chen DJ
通讯作者：
Chen DJ