Department of Medical Oncology, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc and Institut de Recherche Expérimentale et Clinique (Pôle MIRO), Université catholique de Louvain, Brussels, Belgium; Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
Statistical Support Unit, King Albert II Cancer Institute, Cliniques universitaires Saint-Luc, Brussels, Belgium.
Crit Rev Oncol Hematol. 2018 Dec;132:138-144. doi: 10.1016/j.critrevonc.2018.09.009. Epub 2018 Sep 14.
Gene-panels are used to assess predisposition to breast cancer by simultaneous testing of multiple susceptibility genes. This approach increases the identification of variants of unknown significance (VUS) that cannot be used in clinical decision-making. We performed a systematic review of published studies to calculate the prevalence of VUS and pathogenic variants (PV) in routinely tested breast cancer susceptibility genes in patients at high risk of breast cancer.
We comprehensively searched the literature using Medline through May 23, 2017 for studies conducting gene-panel testing on germline DNA of women with familial breast cancer and reporting on both PVs and VUSs. A meta-analysis of the collected data was carried out to obtain pooled VUS and PV prevalence estimates per gene using a generalized linear mixed model with logit link for binomial distribution.
Of 602 publications, 4 were eligible and included 1870 patients. The panels encompassed 4-27 considered genes. Overall, the estimated probability per gene of a PV and VUS was 55% (95% confidence interval (CI) 26%-81%) and 91% (95% CI 78%-97%), respectively (p = 0.0066). The estimated probability per patient of a PV and VUS was 8% (95% CI 1%-34%) and 23% (95% CI 7%-52%), respectively (p = 0.0052). The ratio of VUS to PV was highest in the mismatch repair genes MLH1, MSH2, MSH6, PMS2 (18.7), CDH1 (13.4) and ATM (9.5). Amongst the 1468 patients tested for BRCA1 and BRCA2, only these two genes had a VUS to PV ratio of less than one (0.2 and 0.6, respectively).
With the current panels, the probability of detecting a VUS is significantly higher than the probability of detecting a PV. Better classification of VUSs is therefore critical and requires gene-specific VUS-assessment in every future study of gene-panel testing in patients at high risk of breast cancer.
基因面板通过同时检测多个易感性基因来评估乳腺癌的易感性。这种方法增加了无法用于临床决策的未知意义变异体 (VUS) 的识别。我们对已发表的研究进行了系统评价，以计算高乳腺癌风险患者中常规检测的乳腺癌易感性基因中 VUS 和致病性变异体 (PV) 的患病率。
我们使用 Medline 通过 2017 年 5 月 23 日全面搜索文献，对进行家族性乳腺癌女性种系 DNA 基因面板检测并报告 PV 和 VUS 的研究进行了综合分析。使用广义线性混合模型对数二项分布进行分析，以获得每个基因的汇总 VUS 和 PV 患病率估计值。
在 602 篇论文中，有 4 篇符合条件并纳入了 1870 名患者。面板涵盖了 4-27 个被认为的基因。总体而言，每个基因的 PV 和 VUS 的概率估计值分别为 55%（95%CI 26%-81%）和 91%（95%CI 78%-97%）（p=0.0066）。每个患者的 PV 和 VUS 概率估计值分别为 8%（95%CI 1%-34%）和 23%（95%CI 7%-52%）（p=0.0052）。在错配修复基因 MLH1、MSH2、MSH6、PMS2（18.7）、CDH1（13.4）和 ATM（9.5）中，VUS 与 PV 的比值最高。在 1468 名接受 BRCA1 和 BRCA2 检测的患者中，只有这两个基因的 VUS 与 PV 的比值小于 1（分别为 0.2 和 0.6）。
目前的面板检测，检测到 VUS 的概率明显高于检测到 PV 的概率。因此，更好地分类 VUS 至关重要，需要在未来每一项针对高乳腺癌风险患者基因面板检测的研究中进行特定基因的 VUS 评估。
