Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Department of Pathology, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Bioinformatics. 2021 Jun 16;37(10):1452-1460. doi: 10.1093/bioinformatics/btaa965.
Quantitative immunofluorescence is often used for immunohistochemistry quantification of proteins that serve as cancer biomarkers. Advanced image analysis systems for pathology allow capturing expression levels in each individual cell or subcellular compartment. However, only the mean signal intensity within the cancer tissue region of interest is usually considered as biomarker completely ignoring the issue of tumor heterogeneity.
We propose using immunohistochemistry image-derived information on the spatial distribution of cellular signal intensity (CSI) of protein expression within the cancer cell population to quantify both mean expression level and tumor heterogeneity of CSI levels. We view CSI levels as marks in a marked point process of cancer cells in the tissue and define spatial indices based on conditional mean and conditional variance of the marked point process. The proposed methodology provides objective metrics of cell-to-cell heterogeneity in protein expressions that allow discriminating between different patterns of heterogeneity. The prognostic utility of new spatial indices is investigated and compared to the standard mean signal intensity biomarkers using the protein expressions in tissue microarrays incorporating tumor tissues from 1000+ breast cancer patients.
Supplementary data are available at Bioinformatics online.
定量免疫荧光常用于作为癌症生物标志物的蛋白质的免疫组织化学定量。用于病理学的先进图像分析系统允许在每个单个细胞或亚细胞隔室中捕获表达水平。然而，通常仅考虑作为生物标志物的感兴趣区域中癌症组织内的平均信号强度，完全忽略了肿瘤异质性的问题。
我们建议使用免疫组织化学图像中有关细胞信号强度（CSI）在癌症细胞群体中蛋白表达的空间分布的信息，来定量 CSI 水平的平均表达水平和肿瘤异质性。我们将 CSI 水平视为组织中癌细胞的标记点过程中的标记，并基于标记点过程的条件均值和条件方差定义空间指数。所提出的方法提供了蛋白质表达中细胞间异质性的客观度量标准，允许区分不同的异质性模式。使用包含 1000 多个乳腺癌患者肿瘤组织的组织微阵列中的蛋白表达，研究了新的空间指数的预后效用，并与标准平均信号强度生物标志物进行了比较。
补充数据可在“Bioinformatics”在线获取。
