Pan-Cancer Analysis for Immune Cell Infiltration and Mutational Signatures Using Non-Negative Canonical Correlation Analysis

Simple Summary Mutational signatures have been used to infer links between tumor development and mutational processes. However, the functional roles of mutational signatures in tumor cells and their influence on the tumor microenvironment remain unclear. This study investigates the impact of tumor microenvironments and immune activities on mutational signatures using integrative analysis of whole-exome sequencing and RNA sequencing data obtained from the same patients. This study applies non-negative canonical correlation analysis to the datasets and identifies the mutational signatures related to the immune cell infiltration in each tumor type. This approach helps to search for the survival and immunological aspects of the mutational signatures in tumors. Mutational signatures indicate the mutational processes and substitution patterns in cancer cell genomes. However, the functional consequences of mutational signatures remain unclear, and there have been no comprehensive systematic studies to examine the relationships between the mutational signatures and the immune cell infiltration. Here, the relationship between mutational signatures and immune cell infiltration using non-negative canonical correlation analysis based on 8927 patients across 25 tumor types was investigated. By inspecting mutational signatures with the maximal coefficients determined by the non-negative canonical correlation analysis, the study identified mutational signatures related to immune cell infiltration composed of tumor microenvironments. The analysis was validated by showing that the genes associated with the identified mutational signatures were linked to overall survival by a Kaplan-Meier curve and a log-rank test and were mainly related to immunity by gene set enrichment analysis. These results will help expand our knowledge of tumor biology and recognize the functional roles and associations of immune systems with mutational signatures.