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Abstract：
Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT).
We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls.
A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results.
We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.
We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1-CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case-control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls.
A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)-like (N = 226). We then examined their association with breast cancer risk in the case-control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35-3.41), 1.57 (95% CI, 1.41-1.75), and 1.19 (95% CI, 1.08-1.31), respectively. The meta-analysis of population-specific datasets showed similar results.
We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436; 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.
摘要：
■CHEK2中的生殖系致病变异赋予中度升高的乳腺癌风险(比值比，OR〜2.5)，用于增强乳腺癌筛查的合格携带者。除了致病变异,已鉴定出数十种意义不确定的错义CHEK2变体（VUS），阻碍了生殖系基因检测(GGT)的临床应用。
■我们在15个国家收集了由ENIGMA联盟确定的460个CHEK2错觉VUS。使用CHEK2互补测定定量人RPE1-CHEK2敲除细胞中的KAP1磷酸化和CHK2自磷酸化进行其功能表征。两种功能测定的一致结果用于从12个ENIGMA病例对照数据集中对CHEK2VUS进行分类，包括73,048名女性乳腺癌患者和88,658名种族匹配的对照。
■总共成功分析了430/460VUS，其中340（79.1％）在两种功能测定中均一致，并归类为功能受损（N=102），功能中间（N=12），或功能野生型(WT)样(N=226)。然后，我们在病例对照分析中检查了它们与乳腺癌风险的关联。功能受损携带者的OR和95%CI(置信区间)，中间,WT样变异为2.83（95%CI，2.35-3.41），1.57（95%CI，1.41-1.75），和1.19（95%CI，1.08-1.31），分别。对特定人群数据集的荟萃分析显示出类似的结果。
■我们确定了在乳腺癌患者中发现的大多数CHEK2错义VUS的功能后果（3,660/4,436；82.5％）。功能性受损错义变异的携带者占乳腺癌患者的0.5%，并且与截短CHEK2变异的中等风险相似。相比之下,所有乳腺癌患者中有2.2％携带功能野生型/中间错义变异，在杂合子携带者中没有临床相关的乳腺癌风险。
■我们在15个国家收集了由ENIGMA联盟确定的460个CHEK2错觉VUS。使用CHEK2互补测定定量人RPE1-CHEK2敲除细胞中的KAP1磷酸化和CHK2自磷酸化进行其功能表征。两种功能测定的一致结果用于从12个ENIGMA病例对照数据集中对CHEK2VUS进行分类，包括73,048名女性乳腺癌患者和88,658名种族匹配的对照。
■总共成功分析了430/460VUS，其中340（79.1％）在两种功能测定中均一致，并归类为功能受损（N=102），功能中间（N=12），或功能野生型(WT)样(N=226)。然后，我们在病例对照分析中检查了它们与乳腺癌风险的关联。功能受损携带者的OR和95%CI(置信区间)，中间,WT样变异为2.83（95%CI，2.35-3.41），1.57（95%CI，1.41-1.75），和1.19（95%CI，1.08-1.31），分别。对特定人群数据集的荟萃分析显示出类似的结果。
■我们确定了在乳腺癌患者中发现的大多数CHEK2错义VUS的功能后果（3,660/4,436；82.5％）。功能性受损错义变异的携带者占乳腺癌患者的0.5%，并且与截短CHEK2变异的中等风险相似。相比之下,所有乳腺癌患者中有2.2％携带功能野生型/中间错义变异，在杂合子携带者中没有临床相关的乳腺癌风险。
