A Mutational Signature that Predicts Prognosis and Benefit of Immune Checkpoint Blockade in Colorectal Cancer

Abstract

Background: Colorectal cancer (CRC) is characterized by broad genomic and transcriptional heterogeneity. However, the genomic basis of this variability remains poorly understood. Our pilot study identi ed mutated genes were associated with immune in ltration. This study aims to explore a novel mutational signature (MS) in tumor microenvironment (TME) of CRC. Methods: We integrated single nucleotide variation and transcriptome data and collected corresponding clinicopathologic information from 1,133 and 588 CRC patients of Memorial Sloan Kettering Cancer Center and The Cancer Genome Atlas databases, respectively. Single sample gene set enrichment analysis (ssGSEA) was used to identify the subtypes of CRC based on the immune genomes of 29 immune signatures. CIBERSORT was used to analyze the in ltration of 22 immune cell types in the TME and immune-related gene expression CRC tissues. Results: In the training cohort, we identi ed a novel MS consisting of 27 genes and generated a prognostic model that classi es patients into high-and low-risk groups. The low-risk group was associated with better survival and more tumor mutational burden, microsatellite instability, and mismatch repair de ciency. The data were all veri ed in the validation set. Further analysis revealed that the MS was associated with tumor immunogenicity and immunocyte in ltration, and the determined risk score (RS) could be an index for the immunity level. Conclusion: We identi ed a MS that could assist clinicians to select immunotherapy responsive patients and the combination of RS and TNM stage could provide comprehensive prognostic information for CRC.