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

Abstract

Introduction: 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. Methods:The DNA sequencing and gene expression profiling of CRC patients were extracted from TCGA and MD Anderson Cancer Center databases, with validation utilizing external databases, and correlation between ARID1A and immunologic features. Immunohistochemistry for T-cell markers was performed on a separate cohort of patients.Results: 28/417 MSS CRC patients (6.7%) had ARID1A mutation. Among 58 genes most commonly mutated in CRC, 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 IFN-γ 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 genes 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). Conclusion:The immunogenicity of ARID1A mutant cases 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.

Multi-Omics Data Analyses Construct a Six Immune-Related Genes Prognostic Model for Cervical Cancer in Tumor Microenvironment

“…Additionally, we subsequently focused on investigating genetic alternations and speculating about their potential functions by comparing the somatic mutations between the high- and low-immunity cohorts. Moreover, the results demonstrated that 32 genes mutated differently, which were thought to mainly participate in immunobiological pathways, such as T cell activation, PD-L1-mediated immune escape, and T helper cell differentiation ( Heinonen et al, 2015 ; Shen et al, 2018 ; Li et al, 2019 ; Jung et al, 2021 ; Mehrvarz Sarshekeh et al, 2021 ). Interestingly, some altered genes have the potential to regulate the immunometabolism and neuroinflammation ( Kataria et al, 2019 ; Turner et al, 2019 ; Sheetz et al, 2020 ), which may participate in the metabolic cross-talk between tumor cells and surrounding immune-infiltrating cells.…”

Loss of ARID1A Expression is Associated with Systemic Inflammation Markers and has Important Prognostic Significance in Gastric Cancer.

“…With the rapid development of immunotherapy, some systemic in ammatory markers (such as NLR, PLR, CRP, albumin, etc) have been found to be closely related to the prognosis of ICIs in different kinds of tumors (Dharmapuri et al 2020;Formica et al 2020;Rossi et al 2020). ARID1A mutation has been reported as an independent predictor of longer PFS during tumor immunotherapy (Okamura et al 2020), and is closely related to increased expression of gene signatures of immune checkpoint, cytotoxic T-cell function and antigen presentation(Mehrvarz Sarshekeh et al 2021). Increased expression of key genes (HAVCR2, IDO1, IL4I1, LAG3, PDCD1, PDCD1LG and THFRSF4) which are known to be related to immune response are also associated with ARID1A mutation(Mehrvarz Sarshekeh et al 2021).…”

“…ARID1A mutation has been reported as an independent predictor of longer PFS during tumor immunotherapy (Okamura et al 2020), and is closely related to increased expression of gene signatures of immune checkpoint, cytotoxic T-cell function and antigen presentation(Mehrvarz Sarshekeh et al 2021). Increased expression of key genes (HAVCR2, IDO1, IL4I1, LAG3, PDCD1, PDCD1LG and THFRSF4) which are known to be related to immune response are also associated with ARID1A mutation(Mehrvarz Sarshekeh et al 2021). In our study, we found loss of ARID1A protein was associated with lower albumin (p=0.0064) and low ARID1A mRNA was associated with higher PLR (p=0.0689).…”

ARID1A Mutation in Metastatic Breast Cancer: A Potential Therapeutic Target

“…Previous preclinical and clinical studies have reported that ARID1A mutation can enhance the immunogenicity of tumor cells in breast cancer ( 107 ) and improve tumor sensitivity to immune checkpoint inhibitors in various cancers, including metastatic urothelial cancer ( 108 ), advanced nonsmall cell lung cancer ( 109 ), ovarian clear cell cancer ( 110 ), colorectal cancer ( 111 , 112 ), gastrointestinal cancer ( 113 ), and colon cancer ( 114 ), which can provide insights into ARID1A-mutated breast cancer. Meanwhile, ATM inhibitors and HDAC6 inhibitors can further potentiate the efficacy of antitumor immunity in ARID1A-mutated ovarian cancer ( 115 , 116 ).…”