用病理图像预测癌症甲基化状态,准确率比现有方法高20%以上。
A Novel Approach to Linking Histology Images with DNA Methylation
- 基于图神经网络的弱监督学习框架,从病理全片图像推断基因组甲基化状态。
- 在3个癌症队列中,甲基化预测的AUROC提升超20%,显著优于当前最优方法。
- 揭示了组织形态与基因甲基化模式的空间关联,适合肿瘤生物标志物研究者。
DNA甲基化是一种通过向DNA添加甲基基团调控基因表达的表观遗传机制,异常甲基化模式可导致基因表达紊乱并关联癌症发生。目前定量甲基化的检测依赖专门实验,成本高、耗时长,难以在临床普及。相比之下,多数癌症患者的全切片图像(WSIs)更为易得。因此,探索WSIs与甲基化模式之间的关系具有重要意义。本文提出一种端到端的图神经网络为基础的弱监督学习框架,用于预测在样本间呈现一致模式的基因组甲基化状态。利用来自TCGA的三个队列数据——TCGA-LGG(n=729)、TCGA-GBM(n=729)和TCGA-KIRC(n=511),结果表明该方法在甲基化预测上的AUROC得分显著高于现有最优方法,提升超过20%。对预测出的基因组进行富集分析显示,多数基因组显著富集于重要癌症特征与通路。此外,我们生成了空间富集热图,进一步探究组织学模式与甲基化状态之间的关联。据我们所知,这是首个使用弱监督深度学习,在多种癌症类型中探索空间解析的组织学模式与基因组甲基化状态之间关联的研究。
原文摘要 · Abstract (English)
DNA methylation is an epigenetic mechanism that regulates gene expression by adding methyl groups to DNA. Abnormal methylation patterns can disrupt gene expression and have been linked to cancer development. To quantify DNA methylation, specialized assays are typically used. However, these assays are often costly and have lengthy processing times, which limits their widespread availability in routine clinical practice. In contrast, whole slide images (WSIs) for the majority of cancer patients can be more readily available. As such, given the ready availability of WSIs, there is a compelling need to explore the potential relationship between WSIs and DNA methylation patterns. To address this, we propose an end-to-end graph neural network based weakly supervised learning framework to predict the methylation state of gene groups exhibiting coherent patterns across samples. Using data from three cohorts from The Cancer Genome Atlas (TCGA) - TCGA-LGG (Brain Lower Grade Glioma), TCGA-GBM (Glioblastoma Multiforme) ($n$=729) and TCGA-KIRC (Kidney Renal Clear Cell Carcinoma) ($n$=511) - we demonstrate that the proposed approach achieves significantly higher AUROC scores than the state-of-the-art (SOTA) methods, by more than $20\%$. We conduct gene set enrichment analyses on the gene groups and show that majority of the gene groups are significantly enriched in important hallmarks and pathways. We also generate spatially enriched heatmaps to further investigate links between histological patterns and DNA methylation states. To the best of our knowledge, this is the first study that explores association of spatially resolved histological patterns with gene group methylation states across multiple cancer types using weakly supervised deep learning.
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