RAD50 germline mutations are associated with poor survival in BRCA1/2-negative breast cancer patients
RAD50 germline mutations are associated with poor survival in BRCA1/2-negative breast cancer patients
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RAD50。
DOI：
10.1002/ijc.31579
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发表时间：
2018-10-15
影响因子：
6.4
通讯作者：
Xie, Yuntao
中科院分区：
文献类型：
--
作者：
Fan, Cong;Zhang, Juan;Xie, Yuntao
RAD 50是一个高度保守的DNA双链断裂（DSB）修复基因。然而，RAD 50生殖系突变与乳腺癌生存率和风险之间的关系尚未完全阐明。在这里，我们的目的是研究RAD 50生殖系突变在一个大的乳腺癌患者队列中的临床影响。在我们的研究中，使用新一代测序技术在7657例无BRCA 1/2突变的连续性乳腺癌患者中确定了RAD 50生殖系突变。我们还使用桑格测序在5000名健康对照中筛查了RAD 50复发突变（L719 fs、K994 fs和H1269 fs）。我们发现7，657例患者中有26例（0.34%）携带RAD 50致病突变，其中16例患者携带三种复发突变之一（L719 fs，n=6例; K994 fs，n=5例;和H1269 fs，n = 5例）;复发突变率为0.21%。在5,000名健康对照中，三种复发突变的频率为0.18%（9/5,000）。这些突变并未增加研究患者的乳腺癌风险[比值比（OR），1.16; 95%置信区间（CI），0.51-2.63; p=0.72]。然而，多变量分析显示，RAD 50致病性突变是无复发生存期（RFS）[校正风险比（HR）2.66; 95%CI，1.18-5.98; p=0.018]和疾病特异性生存期的独立不利预测因子。（DSS;校正HR 4.36; 95% CI，1.58-12.03; p = 0.004）。我们的研究表明，RAD 50生殖系突变与乳腺癌风险增加无关，但与没有这些突变的患者相比，RAD 50生殖系突变患者的生存率不利。
RAD50 is a highly conserved DNA double-strand break (DSB) repair gene. However, the associations between RAD50 germline mutations and the survival and risk of breast cancer have not been fully elucidated. Here, we aimed to investigate the clinical impact of RAD50 germline mutations in a large cohort of unselected breast cancer patients. In our study, RAD50 germline mutations were determined using next-generation sequencing in 7657 consecutive unselected breast cancer patients without BRCA1/2 mutations. We also screened for RAD50 recurrent mutations (L719fs, K994fs, and H1269fs) in 5000 healthy controls using Sanger sequencing. We found that 26 out of 7,657 (0.34%) patients had RAD50 pathogenic mutations, and 16 patients carried one of the three recurrent mutations (L719fs, n=6 cases; K994fs, n=5 cases; and H1269fs, n = 5 cases); the recurrent mutation rate was 0.21%. The frequency of the three recurrent mutations in the 5,000 healthy controls was 0.18% (9/5,000). These mutations did not confer an increased risk of breast cancer in the studied patients [odds ratios (OR), 1.16; 95% confidence interval (CI), 0.51-2.63; p=0.72]. Nevertheless, multivariate analysis revealed that RAD50 pathogenic mutations were an independent unfavourable predictor of recurrence-free survival (RFS) [adjusted hazard ratio (HR) 2.66; 95% CI, 1.18-5.98; p=0.018] and disease-specific survival (DSS; adjusted HR 4.36; 95% CI, 1.58-12.03; p = 0.004) in the entire study cohort. Our study suggested that RAD50 germline mutations are not associated with an increased risk of breast cancer, but patients with RAD50 germline mutations have unfavourable survival compared to patients without these mutations.