## 3 Results
### Genesets Associated with the Identified Mutational Signatures  
To further validate the approach used, this study performed GSEA [40] against a pre-ranked list of genes (GSEApreranked) by the PCCs between the mutational signatures and the expression values of the genes. Figure 5 shows the results of GSEApreranked with pre-defined GO BP genesets for nine tumor types (BRCA, HNSC, LGG, LUAD, LUSC, PRAD, SKCM, THCA, and UCEC) with the largest number of samples (>450 samples), and Supplementary Tables S1-S50 show the complete results with FDR < 0.25 for all tumor types. When firstly showing the enriched GO BP terms based on the positively correlated gene, in BRCA, immune-related terms such as adaptive immune response, antigen receptor-mediated signaling pathway, and immune response regulating cell surface receptor signaling pathway were mainly observed. These properties have also been observed in other tumor types. For example, in HNSC and LUSC, the GO BP terms with the lowest FDR values were adaptive immune response, antigen processing, and presentation of peptide antigen with FDR \(<1.0\times 10^{-6}\). For SKCM, terms such as natural killer cell-mediated immunity (FDR = 0.0094), positive regulation of natural killer cell-mediated cytotoxicity (FDR = 0.010), and regulation of natural killer cell-mediated immunity (FDR = 0.012) were among the top five GO BP terms. In addition, for THCA, GO BP terms, such as adaptive immune response, immune response regulating cell surface receptor signaling pathway, and leukocyte-mediated immunity, were uncovered with FDR \(<1.0\times 10^{-6}\). For LGG, brain-related terms, such as neurons or synapses, were primarily discovered, but some immune-related terms, including antigen processing and presentation of peptide antigen via MHC class I (FDR = 0.030) were also enriched. In some tumor types, negatively correlated genes were mainly enriched in immune-related terms. In LUAD, the two terms with the lowest FDR values were the B cell receptor signaling pathway (FDR \(<1.0\times 10^{-6}\)) and phagocytosis recognition (FDR = 0.0060). In addition, in UCEC, terms for GO BP such as adaptive immune response (FDR \(<1.0\times 10^{-6}\)) and B cell receptor signaling pathway (FDR \(<1.0\times 10^{-6}\)) were mainly observed. In addition, GSEApreranked results using other tumor types not represented in Figure 5 also revealed that immune-related terms were highly enriched. For instance, the top-ranked GO BP terms for positively correlated genes in BLCA were the B cell receptor signaling pathway (FDR = 0.0036). In KIRC, terms such as negative regulation of immune response (FDR = \(3.01\times 10^{-5}\)), positive regulation of interleukin 4 production (FDR = \(3.12\times 10^{-5}\)), and negative regulation of immune system processes (FDR = \(3.15\times 10^{-5}\)) were frequently observed. Furthermore, when searching for negatively correlated genes, for COAD, many of the enriched GO terms for negatively correlated genes were immune-related, including activation of the immune response, adaptive immune response, antigen receptor-mediated signaling pathway, and B cell-mediated immunity, whose FDRs were lower than \(1.0\times 10^{-6}\). As another example, STAD also revealed many immune-related terms with statistical significance, including B cell receptor signaling pathway (FDR \(5.83\times 10^{-5}\)), B cell homeostasis (FDR = 0.0050), antigen processing and presentation of exogenous antigen (FDR = 0.0053), regulation of leukocyte adhesion to vascular endothelial cells (FDR = 0.0073), and antigen processing and presentation of exogenous peptide antigen (FDR = 0.0075). Figure 5: Enriched genesets detected by the GSEAPreranked approach. Barplots show the -log FDR values for the top three GO BP terms based on GSEAPreranked. Enrichment results for positively correlated genes are represented in red, and negatively correlated genes are represented in blue. GO BP terms with the same FDR values were ordered by the absolute value of the normalized enrichment score (NES) generated using the GSEA tool.