Yang Yunqi, Hong Christine, Liang Jane W, Gruber Stephen, Parmigiani Giovanni, Idos Gregory, Braun Danielle
Committee on Genetics, Genomics and Systems Biology, The University of Chicago, Chicago, Illinois, USA.
Keck School of Medicine, University of Southern California, Los Angeles, California, USA.
Stat Med. 2021 Feb 10;40(3):593-606. doi: 10.1002/sim.8791. Epub 2020 Oct 29.
Commercialized multigene panel testing brings unprecedented opportunities to understand germline genetic contributions to hereditary cancers. Most genetic testing companies classify the pathogenicity of variants as pathogenic, benign, or variants of unknown significance (VUSs). The unknown pathogenicity of VUSs poses serious challenges to clinical decision-making. This study aims to assess the frequency of VUSs that are likely pathogenic in disease-susceptibility genes. Using estimates of probands' probability of having a pathogenic mutation (ie, the carrier score) based on a family history probabilistic risk prediction model, we assume the carrier score distribution for probands with VUSs is a mixture of the carrier score distribution for probands with positive results and the carrier score distribution for probands with negative results. Under this mixture model, we propose a likelihood-based approach to assess the frequency of pathogenicity among probands with VUSs, while accounting for the existence of possible pathogenic mutations on genes not tested. We conducted simulations to assess the performance of the approach and show that under various settings, the approach performs well with very little bias in the estimated proportion of VUSs that are likely pathogenic. We also estimate the positive predictive value across the entire range of carrier scores. We apply our approach to the USC-Stanford Hereditary Cancer Panel Testing cohort, and estimate the proportion of probands that have VUSs in BRCA1/2 that are likely pathogenic to be 10.12% [95%CI: 0%, 43.04%]. This approach will enable clinicians to target high-risk patients who have VUSs, allowing for early prevention interventions.
商业化的多基因检测 panel 为了解种系基因对遗传性癌症的贡献带来了前所未有的机遇。大多数基因检测公司将变异的致病性分类为致病性、良性或意义未明的变异（VUS）。VUS 的致病性未知给临床决策带来了严峻挑战。本研究旨在评估疾病易感性基因中可能致病的 VUS 的频率。基于家族史概率风险预测模型，利用先证者携带致病突变概率（即携带者分数）的估计值，我们假设携带 VUS 的先证者的携带者分数分布是检测结果为阳性的先证者和检测结果为阴性的先证者的携带者分数分布的混合。在这种混合模型下，我们提出了一种基于似然的方法来评估携带 VUS 的先证者中致病性的频率，同时考虑未检测基因上可能存在的致病突变。我们进行了模拟以评估该方法的性能，并表明在各种设置下，该方法表现良好，在估计可能致病的 VUS 的比例时偏差很小。我们还估计了整个携带者分数范围内的阳性预测值。我们将我们的方法应用于南加州大学 - 斯坦福遗传性癌症检测 panel 队列，并估计在 BRCA1/2 中携带 VUS 且可能致病的先证者比例为 10.12% [95%CI：0%，43.04%]。这种方法将使临床医生能够针对携带 VUS 的高危患者，从而实现早期预防干预。
