ARID1A Mutation May Define an Immunologically Active Subgroup in Patients with Microsatellite Stable Colorectal Cancer

Abstract

Purpose: ARID1A is commonly mutated in colorectal cancer (CRC), frequently resulting in truncation and loss of protein expression. ARID1A recruits MSH2 for mismatch-repair during DNA replication. ARID1A deficiency promotes hypermutability and immune activation in preclinical models but its role in CRC patients is being explored. Experimental Design: The DNA sequencing and gene expression profiling of CRC patients were extracted from TCGA and MDACC databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. Immunohistochemistry for T-cell markers was performed on a separate cohort. Results: 28/417 MSS CRC patients (6.7%) had ARID1A mutation. Among 58 genes most commonly mutated in CRC, ARID1A had the highest increase with frameshift mutation rates in MSS cases (8-fold, pARID1A mutation was enriched in immune subtype (CMS1) and had a strong correlation with IFN-γ expression (Δz score +1.91, pARID1A wild-type, statistically significant higher expression for key checkpoint genes (PD-L1, CTLA4, and PDCD1) and genes sets (e.g., antigen presentation, cytotoxic T cell function, and immune checkpoints) was observed in ARID1A mutants. This was validated by unsupervised differential expression of genes related to immune response and further, confirmed by higher infiltration of T-cells in IHC of tumors with ARID1A mutation (p=0.01). Conclusions: The immunogenicity of ARID1A mutation is likely due to increased level of neoantigens resulting from increased TMB and frameshift mutations. Tumors with ARID1A mutation may be more susceptible to immune therapy-based treatment strategies and should be recognized as a unique molecular subgroup in future immune therapy trials.