Correlation Analysis of Histopathology and Proteogenomics Data for Breast Cancer*

Histopathology images are important for cancer diagnosis and prognosis. We extracted quantitative morphological features from breast cancers images and systematically analyzed their relationships with proteins and mRNAs. We observed concordant correlation patterns between image-protein and image-RNA and identified four cancer-related biological processes associated with morphological features related to different tumor components. Further, we observed that proteomic data reveal unique protein-related biological processes associated with morphology. Finally, prognostic morphological features were identified, and their roles are consistent with the underlying biological processes. Graphical Abstract Highlights Consistent correlation patterns between image-protein and image-mRNA at genome level. Four major biological processes associated with cellular and tissue morphology. Proteomic data reveal protein-specific biology processes associated with morphology. Morphological features can predict survival with relevant molecular events. Tumors are heterogeneous tissues with different types of cells such as cancer cells, fibroblasts, and lymphocytes. Although the morphological features of tumors are critical for cancer diagnosis and prognosis, the underlying molecular events and genes for tumor morphology are far from being clear. With the advancement in computational pathology and accumulation of large amount of cancer samples with matched molecular and histopathology data, researchers can carry out integrative analysis to investigate this issue. In this study, we systematically examine the relationships between morphological features and various molecular data in breast cancers. Specifically, we identified 73 breast cancer patients from the TCGA and CPTAC projects matched whole slide images, RNA-seq, and proteomic data. By calculating 100 different morphological features and correlating them with the transcriptomic and proteomic data, we inferred four major biological processes associated with various interpretable morphological features. These processes include metabolism, cell cycle, immune response, and extracellular matrix development, which are all hallmarks of cancers and the associated morphological features are related to area, density, and shapes of epithelial cells, fibroblasts, and lymphocytes. In addition, protein specific biological processes were inferred solely from proteomic data, suggesting the importance of proteomic data in obtaining a holistic understanding of the molecular basis for tumor tissue morphology. Furthermore, survival analysis yielded specific morphological features related to patient prognosis, which have a strong association with important molecular events based on our analysis. Overall, our study demonstrated the power for integrating multiple types of biological data for cancer samples in generating new hypothesis as well as identifying potential biomarkers predicting patient outcome. Future work includes causal analysis to identify key regulators for cancer tissue development and validating the findings using more independent data sets.