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首页> 美国卫生研究院文献>International Journal of Molecular Sciences >Towards a New Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants
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Towards a New Endophenotype-Based Strategy for Pathogenicity Prediction in BRCA1 and BRCA2: In Silico Modeling of the Outcome of HDR/SGE Assays for Missense Variants

机译：朝向BRCA1和BRCA2中的致病性预测致病性预测的基于新的内酚型策略：在Missense Variants的HDR / SGE测定结果的硅模型中

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摘要

The present limitations in the pathogenicity prediction of BRCA1 and BRCA2 (BRCA1/2) missense variants constitute an important problem with negative consequences for the diagnosis of hereditary breast and ovarian cancer. However, it has been proposed that the use of endophenotype predictions, i.e., computational estimates of the outcomes of functional assays, can be a good option to address this bottleneck. The application of this idea to the BRCA1/2 variants in the CAGI 5-ENIGMA international challenge has shown promising results. Here, we developed this approach, exploring the predictive performances of the regression models applied to the BRCA1/2 variants for which the values of the homology-directed DNA repair and saturation genome editing assays are available. Our results first showed that we can generate endophenotype estimates using a few molecular-level properties. Second, we show that the accuracy of these estimates is enough to obtain pathogenicity predictions comparable to those of many standard tools. Third, endophenotype-based predictions are complementary to, but do not outperform, those of a Random Forest model trained using variant pathogenicity annotations instead of endophenotype values. In summary, our results confirmed the usefulness of the endophenotype approach for the pathogenicity prediction of the BRCA1/2 missense variants, suggesting different options for future improvements.
机译：BRCA1和BRCA2（BRCA1 / 2）的致病性预测的本限制（BRCA1 / 2）的致命变异构成了对遗传性乳腺癌和卵巢癌的诊断负面影响的重要问题。然而，已经提出了使用内切型预测，即功能测定结果的计算估计，可以是解决这个瓶颈的良好选择。这个想法在Cagi 5-Enigma国际挑战中的BRCA1 / 2变体中的应用表明了有希望的结果。在这里，我们开发了这种方法，探讨了应用于BRCA1 / 2变体的回归模型的预测性能，其可获得同源定向的DNA修复和饱和基因组的值。我们的结果首先表明我们可以使用少数分子水平性能产生内霉素估计。其次，我们表明这些估计的准确性足以获得与许多标准工具相当的致病性预测。第三，基于内切蛋白类型的预测是互补的，但不优于使用变体致病性注释培训的随机森林模型的预测，而不是Endophootype值。总之，我们的结果证实了Endophootype方法对BRCA1 / 2次密封变种的致病性预测的有用性，表明未来改进的不同选择。

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