Cancer Epigenetic Driver Mutations in ARID1A

Cancer Epigenetic Driver Mutations in ARID1A

ARID1A gene research may yield insight into cancer and cancer treatments. Learn more about this gen and the role it plays in cancer epigenetics.

 

In this article:

  1. Mutation and Interactions
  2. ARID1A and Patient Survival
  3. ARID1A Shapes Cancer Immune Phenotype and Immunotherapy
  4. Implications of Findings

ARID1A Mutations Affect Various Types Of Cancer

 

Mutation and Interactions

DNA molecule research | Mutation and Interactions | Cancer Epigenetic Driver Mutations in ARID1A

ARID1A has the highest mutation rate across all components in the SWI/SNF complex. ARID1A mutations occur in many types of human cancers and are notably one of the most frequently mutated genes in cancers. For instance, ovarian clear cell carcinoma has a 50% mutation rate [2], and colorectal adenocarcinomas have an 11% mutation rate [1]. 

SWI/SNF complex mutations are found in 20% of all types of human cancer [3]. 

Compared to the SWI/SNF complex, the polycomb repressive complex 2 (PRC2) has been studied well within the context of cancer biology. There is speculation that there is an antagonistic relationship between Polycomb group Proteins and the SWI/SNF complex [6]. 

Consequently, interest has emerged for understanding whether the interaction between the PRC2 and SWI/SNF complex plays a functional role in shaping cancer immune phenotype and T cell immunity (figure 1) [4]. 

The enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the PRC2, functioning as a methyltransferase, it is a proponent for epigenetic changes affecting the initiation and progression of diseases. EZH2 mediates gene repression and plays an oncogenic role in a variety of cancers. 

It has been shown that EZH2 represses Th1-type chemokine expression and alters effector T cell tumor trafficking [5]. 

Recent findings on ARID1A epigenetic driver mutation’s role in shaping immune phenotype and immunotherapy uncovered if an interaction existed between ARID1A and EZH2. This recent study showed that if this interaction affects T cell immunity and if ARID1A mutations functionally altered the ARID1A and EZH2 interaction in tumors [4].

 

ARID1A and Patient Survival

ARID1A gene status affects patient survival. There was a noticeable outcome when the analysis was run over several types of cancers and the ARID1A gene status. 

The data suggests that the ARID1A gene can affect a patient’s outcome in multiple types of cancer. For instance, patients with ovarian cancer and ARID1A-mutated tumors had poor overall survival compared to patients whose tumors had WT ARID1A (figure 2A). ARID1A mutations were also associated with poor survival in patients with hepatocellular carcinoma (figure 2C) [4]. 

There are correlations between ARID1A gene status and IFN signaling gene signature, T cell tumor infiltration, patient survival, and clinical responses to checkpoint blockade in several types of cancer regardless of tumor mutation load. 

Recent findings support that driver mutations can directly affect tumor T cell immunity and immunotherapy. Cancer epigenetic driver mutations such as ARID1A mutations, shape tumor immune phenotype and drive cancer immune evasion in many types of cancer [4]. 

 

ARID1A Shapes Cancer Immune Phenotype and Immunotherapy

Regardless of the tumor mutation load, ARID1A mutations were associated with reduced clinical benefit in patients who received immunotherapy. The nature of immunosuppressive mechanisms, tumor epigenetics, and tumor metabolism all have a role in determining cancer-immune phenotype and immunotherapy responses. 

Current findings suggest ARID1A gene status has the potential to affect spontaneous and immune checkpoint blockade-induced T cell immunity. 

 

Implications of Findings

Current findings support ARID1A gene status affects cancer immune evasion. ARID1A controls IFN signaling gene chromatin accessibility, which regulates tumor cell response to spontaneous and therapy mediated immune stimulation [4]. Therefore, targeting SWI/SNF complex mutation-associated pathways combined with immunotherapy may be a new approach to treating patients with SWI/SNF cancers. 

In summary, ARID1A mutation is one of the most frequently mutated genes, and its status can affect patient survival. Findings noted that this gene shapes tumor immunity and therapeutic response to immunotherapy across various types of cancer. Furthermore, targeting ARID1A-associated pathways may be an alternative approach to cancer treatments.

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