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

Clin Cancer Res. 2021 Mar 15;27(6):1663-1670. doi: 10.1158/1078-0432.CCR-20-2404. Epub 2021 Jan 7.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • B7-H1 Antigen / genetics
  • B7-H1 Antigen / metabolism*
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • CTLA-4 Antigen / genetics
  • CTLA-4 Antigen / metabolism*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / immunology
  • Colorectal Neoplasms / metabolism
  • Colorectal Neoplasms / pathology*
  • DNA-Binding Proteins / genetics*
  • Follow-Up Studies
  • Gene Expression Profiling
  • Humans
  • Microsatellite Instability
  • Mutation*
  • Prognosis
  • Programmed Cell Death 1 Receptor / genetics
  • Programmed Cell Death 1 Receptor / metabolism*
  • Retrospective Studies
  • T-Lymphocytes, Cytotoxic / immunology*
  • Transcription Factors / genetics*


  • ARID1A protein, human
  • B7-H1 Antigen
  • Biomarkers, Tumor
  • CD274 protein, human
  • CTLA-4 Antigen
  • CTLA4 protein, human
  • DNA-Binding Proteins
  • PDCD1 protein, human
  • Programmed Cell Death 1 Receptor
  • Transcription Factors