Journal Article

Epigenetic-related gene mutations serve as potential biomarkers for immune checkpoint inhibitors in microsatellite-stable colorectal cancer

Liu, Chao, Xiao, Huiting, Ruan, Yuli, Han, Shuling, Zhao, Wenyuan, Cui, Luying, Zhang, Yanqiao, Fang, Lin

2022

Overview

Combination therapy with immune checkpoint inhibitors (ICIs) may benefit approximately 10-20% of microsatellite-stable colorectal cancer (MSS-CRC) patients. However, there is a lack of optimal biomarkers. This study aims to understand the predictive value of epigenetic-related gene mutations in ICIs therapy in MSS-CRC patients. We analyzed DNA sequences and gene expression profiles from The Cancer Genome Atlas (TCGA) to examine their immunological features. The Harbin Medical University Cancer Hospital (HMUCH) clinical cohort of MSS-CRC patients was used to validate the efficacy of ICIs in patients with epigenetic-related gene mutations (Epigenetic_Mut). In TCGA, 18.35% of MSS-CRC patients (78/425) had epigenetic-related gene mutations. The Epigenetic_Mut group had a higher tumor mutation burden (TMB) and frameshift mutation (FS_mut) rates. In all MSS-CRC samples, Epigenetic_Mut was elevated in the immune subtype (CMS1) and had a strong correlation with immunological features. Epigenetic_Mut was also associated with favorable clinical outcomes in MSS-CRC patients receiving anti-PD-1-based therapy from the HMUCH cohort. Using immunohistochemistry and flow cytometry, we demonstrated that Epigenetic_Mut samples were associated with increased anti-tumor immune cells both in tumor tissues and peripheral blood. MSS-CRC patients with epigenetic regulation impairment exhibit an immunologically active environment and may be more susceptible to treatment strategies based on ICIs.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Antigens / biomarker / Biomarkers / Cancer / Clinical outcomes / Colorectal cancer / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - genetics / DNA methylation / Epigenesis, Genetic / epigenetic-related gene mutations / Epigenetics / Flow cytometry / Frameshift mutation / Gene expression / Humans / immune checkpoint inhibitor therapy / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - therapeutic use / Immune response / Immunohistochemistry / Immunology / Lymphocytes / Metabolism / microsatellite-stable / Monoclonal antibodies / Mutation / Nucleotide sequence / Patients / PD-1 protein / Peripheral blood / Point mutation / Tumors