胚系失活变异的 BARD1 基因与早发性家族性乳腺癌相关，但与卵巢癌无关。
Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer.
机构信息
Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Kerpener Str. 34, 50931, Cologne, Germany.
Institute for Human Genetics, University Hospital Muenster, Muenster, Germany.
出版信息
Breast Cancer Res. 2019 Apr 29;21(1):55. doi: 10.1186/s13058-019-1137-9.
BACKGROUND
The role of the BARD1 gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed to assess the role of deleterious BARD1 germline variants in BC/OC predisposition in a sample of 4920 BRCA1/2-negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC).
METHODS
A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in BARD1. All patients met the inclusion criteria of the GC-HBOC for germline testing and reported at least one relative with BC or OC. Additional control datasets (Exome Aggregation Consortium, ExAC; Fabulous Ladies Over Seventy, FLOSSIES) were included for the calculation of odds ratios (ORs).
RESULTS
We identified LoF variants in 23 of 4469 BC index patients (0.51%) and in 36 of 37,265 control individuals (0.10%), resulting in an OR of 5.35 (95% confidence interval [CI] = 3.17-9.04; P < 0.00001). BARD1-mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24-60 years) compared with the overall study sample (48.6 years, range 17-92 years; P = 0.00347). In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78-25.08; P < 0.00001) was observed. An OR of 7.43 (95% CI = 4.26-12.98; P < 0.00001) was observed when stratified for an AAD < 50 years. LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82-6.45; P = 0.11217). Overall, rare and predicted damaging BARD1 missense variants were significantly more prevalent in BC index patients compared with control individuals (OR = 2.15; 95% CI = 1.26-3.67; P = 0.00723). Neither LoF variants nor predicted damaging rare missense variants in BARD1 were identified in 451 familial index patients with OC.
CONCLUSIONS
Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants.
背景
BARD1 基因在乳腺癌（BC）和卵巢癌（OC）易感性中的作用仍不清楚，因为已发表的病例对照研究结果存在争议。我们旨在评估有害 BARD1 种系变异在 4920 名 BRCA1/2 阴性的德国遗传性乳腺癌和卵巢癌（GC-HBOC）女性 BC/OC 指数患者样本中对 BC/OC 易感性的作用。
方法
对 4469 名患有 BC 的女性指数患者、451 名患有 OC 的指数患者和 2767 名具有地理匹配的女性对照个体进行了 BARD1 种系失活（LoF）突变和潜在有害罕见错义变异的筛查。所有患者均符合 GC-HBOC 的种系检测标准，并报告至少有一位亲属患有 BC 或 OC。纳入了额外的对照数据集（外显子组聚合联盟，ExAC；七十多岁的女士们，FLOSSIES），用于计算比值比（OR）。
结果
我们在 4469 名 BC 指数患者中的 23 名（0.51%）和 37265 名对照个体中的 36 名（0.10%）中发现了 LoF 变异，导致 OR 为 5.35（95%置信区间[CI]：3.17-9.04；P<0.00001）。与整个研究样本（48.6 岁，范围 17-92 岁）相比，携带 BARD1 突变的 BC 指数患者的首次诊断平均年龄（AAD；42.3 岁，范围 24-60 岁）明显更小（P=0.00347）。在 AAD<40 岁的 BC 指数患者亚组中，观察到 OR 为 12.04（95%CI：5.78-25.08；P<0.00001）。当 AAD<50 岁分层时，观察到 OR 为 7.43（95%CI：4.26-12.98；P<0.00001）。在 AAD≥50 岁的指数患者亚组中，BARD1 的 LoF 变异与 BC 无显著相关性（OR=2.29；95%CI：0.82-6.45；P=0.11217）。总体而言，与对照个体相比，BC 指数患者中罕见且预测有损害的 BARD1 错义变异更为常见（OR=2.15；95%CI：1.26-3.67；P=0.00723）。在 451 名家族性 OC 指数患者中，未发现 BARD1 的 LoF 变异或预测有损害的罕见错义变异。
结论
由于 BARD1 种系 LoF 变异与早发性 BC 显著相关，我们建议对携带致病性 BARD1 基因突变的女性提供强化的 BC 监测计划。
Zotero 插件