Molecular profiling is central in cancer precision medicine but remains costly and is based on tumor average profiles. Morphologic patterns observable in histopathology sections from tumors are determined by the underlying molecular phenotype and therefore have the potential to be exploited for prediction of molecular phenotypes. We report here the first transcriptome-wide expression–morphology (EMO) analysis in breast cancer, where individual deep convolutional neural networks were optimized and validated for prediction of mRNA expression in 17,695 genes from hematoxylin and eosin–stained whole slide images. Predicted expressions in 9,334 (52.75%) genes were significantly associated with RNA sequencing estimates. We also demonstrated successful prediction of an mRNA-based proliferation score with established clinical value. The results were validated in independent internal and external test datasets. Predicted spatial intratumor variabilities in expression were validated through spatial transcriptomics profiling. These results suggest that EMO provides a cost-efficient and scalable approach to predict both tumor average and intratumor spatial expression from histopathology images. Significance: Transcriptome-wide expression morphology deep learning analysis enables prediction of mRNA expression and proliferation markers from routine histopathology whole slide images in breast cancer.

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从组织病理学图像预测分子表型：乳腺癌的转录组表达形态学分析

分子谱分析是癌症精准医学的核心，但成本仍然很高，而且是基于肿瘤的平均谱。在肿瘤的组织病理学切片中观察到的形态学模式由潜在的分子表型决定，因此有可能被用于预测分子表型。我们在此报告了乳腺癌中的第一个转录组范围表达形态学 (EMO) 分析，其中对单个深度卷积神经网络进行了优化和验证，以预测来自苏木精和伊红染色的整个幻灯片图像的 17,695 个基因的 mRNA 表达。9,334 (52.75%) 个基因的预测表达与 RNA 测序估计显着相关。我们还展示了对基于 mRNA 的增殖评分的成功预测，该评分具有既定的临床价值。结果在独立的内部和外部测试数据集中得到验证。通过空间转录组学分析验证预测的肿瘤内表达空间变异性。这些结果表明，EMO 提供了一种经济高效且可扩展的方法来预测组织病理学图像的肿瘤平均和肿瘤内空间表达。意义：全转录组表达形态学深度学习分析能够预测乳腺癌常规组织病理学全切片图像中的 mRNA 表达和增殖标记。这些结果表明，EMO 提供了一种经济高效且可扩展的方法来预测组织病理学图像的肿瘤平均和肿瘤内空间表达。意义：全转录组表达形态学深度学习分析能够预测乳腺癌常规组织病理学全切片图像中的 mRNA 表达和增殖标记。这些结果表明，EMO 提供了一种经济高效且可扩展的方法来预测组织病理学图像的肿瘤平均和肿瘤内空间表达。意义：全转录组表达形态学深度学习分析能够预测乳腺癌常规组织病理学全切片图像中的 mRNA 表达和增殖标记。