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

Abstract

Purpose: AT-rich interactive domain 1A (ARID1A) is commonly mutated in colorectal cancer, 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 patients with colorectal cancer is being explored.

Experimental design: The DNA sequencing and gene expression profiling of patients with colorectal cancer were extracted from The Cancer Genome Atlas and MD Anderson Cancer Center databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. IHC for T-cell markers was performed on a separate cohort of patients.

Results: Twenty-eight of 417 patients with microsatellite stable (MSS) colorectal cancer (6.7%) had ARID1A mutation. Among 58 genes most commonly mutated in colorectal cancer, ARID1A mutation had the highest increase with frameshift mutation rates in MSS cases (8-fold, P < 0.001). In MSS, ARID1A mutation was enriched in immune subtype (CMS1) and had a strong correlation with IFNγ expression (Δz score +1.91, P < 0.001). Compared with ARID1A wild-type, statistically significant higher expression for key checkpoint genes (e.g., PD-L1, CTLA4, and PDCD1) and gene sets (e.g., antigen presentation, cytotoxic T-cell function, and immune checkpoints) was observed in mutant cases. 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-mutant cases is likely due to an increased level of neoantigens resulting from increased tumor mutational burden 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.

Fig 1.. TMB and frameshift mutation rate in MSS CRC according to the ARID1A mutational status.

A, Violin plot of TMB in ARID1A wt and ARID1A mt in MSS CRC. B, Violin plot of frameshift mutation rate in ARID1A wt and ARID1A mt in MSS CRC.

Fig 2

A, Association of frameshift mutation rate with the mutational status of genes commonly mutated in MSS CRC. B, Association of the differential expression of the IFN-γ pathway and mutational status of genes commonly mutated in MSS CRC.

Fig 3.. The enrichment of ARID1A mutation across different molecular subtype of CRC.

A, Fold enrichment of ARID1A mutation in each molecular subtype in all cases (MSI-H/MSS). B, Fold enrichment of ARID1A mutation in each molecular subtype in MSS CRC.

Fig 4

A, B, RNA expression of gene sets related to immune response in MSS CRC according to the ARID1A mutational status. C, RNA expressions of single genes involved in the immune response in MSS CRC cases according to the ARID1A mutational status.

Fig 5

A1. Infiltration of T lymphocytes in the tumor of patients with MSI-H CRC in ARID1A mt and ARID1A wt cases. A2. Infiltration of T lymphocytes in the tumor of patients with MSS CRC in ARID1A mt and ARID1A wt cases. B, C, Higher intratumoral infiltration of T lymphocytes in an ARID1A mt MSS CRC patient (C) in comparison with that in an ARID1A wt MSS CRC case (B).