ARID1A: gene, protein, and function in endometrial cancer

ARID1A, a key structural subunit of the SWI/SNF chromatin remodeling complex, is the most frequently mutated SWI/SNF subunit in cancer with most mutations occurring in endometrial cancer. In a multitude of malignancies, loss of ARID1A protein correlates with poor patient prognosis, increased metastasis, and changes to key cancer pathways such as genomic instability. Despite this, little work has been done to deduce the molecular role of ARID1A in endometrial cancer progression and prognosis, and much of the present work is conflicting data. There is a growing body of work that shows a discordance between ARID1A mutation status and expression of ARID1A protein in endometrioid-type endometrial tumors. Several other malignancies have found that alternative mechanisms of ARID1A protein regulation can confer ARID1A protein loss. Therefore, relying solely on ARID1A sequencing may overlook a cohort of endometrial cancer patients with absence of ARID1A protein. With endometrial cancer being one of the sole malignancies increasing in both incidence and patient mortality since the mid-2000s, it is of upmost importance to assess the impacts and potential prognostic use of commonly mutated proteins such as ARID1A. This review will highlight the critical role of ARID1A in endometrial cancer pathogenesis, its potential therapeutic vulnerabilities, and emphasizes the need to move beyond ARID1A mutation as a sole diagnostic marker to elucidate its molecular and clinical implications in endometrial cancer.