Heterogeneity Analysis of Esophageal Squamous Cell Carcinoma for Precision Oncology Research

Background: Esophageal Squamous Cell Carcinoma (ESCC), which is the most common pathohistological type of esophageal cancer that accounts for roughly 90% of the 456,000 incidents of esophageal cancer cases each year, is a serious malignant disease, with a 15-20% 5-year survival rate worldwide. The outcome of the current established therapeutics for ESCC are not satisfactory. Heterogeneity, including not only the intratumor heterogeneity and complex micro-environment, but also the diversity of heterogeneity across different ESCC samples, is a major biological feature of cancer that is responsible for the establishment of drug resistance and morbidity. Therefore, the diversity of distinct genotypes and phenotypes contributing to this phenomenon should be analyzed for the purpose of precision research and better understanding of ESCC. Methods: Bioinformatic analysis of multi-omics data from The Cancer Cell Line Encyclopedia (CCLE), The Cancer Genome Atlas (TCGA), and Protein Atlas were conducted to investigate heterogeneity across different ESCC samples. Venn Diagrams were utilized to overlap shared and disparate regions of interest between data platforms. DAVID was used for joint functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathways enrichment. The Cytoscape open source software platform and the STRING database were used for integrating and visualizing complex networks with attribute data. Mutation and expression heterogeneity profiles of CCLE-ESCC and TCGA-ESCC samples were analyzed according to matching dissimilarity and correlation distance, respectively. Findings: Heterogeneity at the level of both gene expression and genomic mutations are widespread in the ESCC tumor tissues and established cell lines. In the analysis of animal model data, we observed that there is ambiguity with regards to the source of nearly 50% of identified proteins, which may indicate the existence of trans-species heterogeneity. Our research also indicate that substantial variability exists between different platforms after overlapping sequencing data from cell lines, tumor tissues, normal tissues and PDX tissues of ESCC . Furthermore, Olfactory transduction and Neuroactive ligand-receptor interaction signaling pathways, enriched from the TCGA-ESCC unique proteins, are originally reported in ESCC. Interpretation: Our research found that extensive mutation heterogeneity exists across the samples of ESCC patients and cell lines. The uniquely expressed proteins and relevant signaling pathways provide potential targets for the investigation of carcinogenesis and progression of ESCC. The identification and characterization of genotype and phenotype heterogeneity across different ESCC samples and platforms is essential for developing precise therapeutics for ESCC patients. Funding Statement: This work was supported by National Natural Science Foundation China (NSFC) [No.81872335], Henan Joint Fund [No.U1804196] and Henan Key Science and Technology Program [161100510300]. Declaration of Interests: The authors have no conflict of interest to declare.