Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer
Germline Mutations in the BRIP1, BARD1, PALB2, and NBN Genes in Women With Ovarian Cancer
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DOI：
10.1093/jnci/djv214
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发表时间：
2015-11-01
影响因子：
10.3
通讯作者：
Gayther, Simon A.
中科院分区：
文献类型：
--
作者：
Ramus, Susan J.;Song, Honglin;Gayther, Simon A.
背景：上皮性卵巢癌 (EOC) 是最致命的妇科恶性肿瘤，在美国每年导致 13 000 人死亡。基于识别卵巢癌易感基因中种系突变的风险预测可能对降低疾病死亡率产生临床上显着的影响。方法：使用下一代测序技术，在 3236 名侵袭性 EOC 病例患者和 3431 名欧洲血统对照患者以及 2000 名来自卵巢癌临床筛查试验的未受影响的高危女性中，识别 4 个候选易感基因（BRIP1、BARD1、PALB2 和 NBN）编码区的种系突变。 （英国FOCSS）。对于每个基因，我们估计了患病率和 EOC 风险，并评估了种系变异状态与临床和流行病学危险因素信息之间的关联。所有统计检验都是双向的。 结果：我们发现，与对照患者 (0.09%) 相比，病例患者 (0.9%) 和 UKFOCSS 参与者 (0.6%) 中 BRIP1 有害突变的频率增加（分别为 P = 1 x 10(-4) 和 8 x 10(-4)），但 BARD1 (P = .39)、NBN1 (P = .61) 或 BARD1 (P = .39) 没有差异。 PALB2（P = .08）。病例患者和对照患者之间 BRIP1 罕见错义变异的频率也存在差异 (P = 5.5 x 10(-4))。侵袭性 EOC 与 BRIP1 突变相关的相对风险为 11.22（95% 置信区间 [CI] = 3.22 至 34.10，P = 1 x 10(-4)），而高级浆液性疾病为 14.09（95% CI = 4.04 至 45.02，P = 2 x 10(-5)）。家庭隔离分析估计，与普通人群相比，BRIP1 突变携带者的平均相对风险为 3.41（95% CI = 2.12 至 5.54，P = 7 x 10(-7)）。结论：BRIP1 的有害种系突变与 EOC 风险中度增加相关。这些数据对卵巢癌的风险预测和预防方法具有临床意义，并强调在中等外显率的基因在癌症预防中具有临床实用性之前，迫切需要基于非常大的样本量进行风险估计。
Background: Epithelial ovarian cancer (EOC) is the most lethal gynecological malignancy, responsible for 13 000 deaths per year in the United States. Risk prediction based on identifying germline mutations in ovarian cancer susceptibility genes could have a clinically significant impact on reducing disease mortality.Methods: Next generation sequencing was used to identify germline mutations in the coding regions of four candidate susceptibility genes-BRIP1, BARD1, PALB2 and NBN-in 3236 invasive EOC case patients and 3431 control patients of European origin, and in 2000 unaffected high-risk women from a clinical screening trial of ovarian cancer (UKFOCSS). For each gene, we estimated the prevalence and EOC risks and evaluated associations between germline variant status and clinical and epidemiological risk factor information. All statistical tests were two-sided.Results: We found an increased frequency of deleterious mutations in BRIP1 in case patients (0.9%) and in the UKFOCSS participants (0.6%) compared with control patients (0.09%) (P = 1 x 10(-4) and 8 x 10(-4), respectively), but no differences for BARD1 (P = .39), NBN1 (P = .61), or PALB2 (P = .08). There was also a difference in the frequency of rare missense variants in BRIP1 between case patients and control patients (P = 5.5 x 10(-4)). The relative risks associated with BRIP1 mutations were 11.22 for invasive EOC (95% confidence interval [CI] = 3.22 to 34.10, P = 1 x 10(-4)) and 14.09 for high-grade serous disease (95% CI = 4.04 to 45.02, P = 2 x 10(-5)). Segregation analysis in families estimated the average relative risks in BRIP1 mutation carriers compared with the general population to be 3.41 (95% CI = 2.12 to 5.54, P = 7 x 10(-7)).Conclusions: Deleterious germline mutations in BRIP1 are associated with a moderate increase in EOC risk. These data have clinical implications for risk prediction and prevention approaches for ovarian cancer and emphasize the critical need for risk estimates based on very large sample sizes before genes of moderate penetrance have clinical utility in cancer prevention.