The Role of ARID1A in Endometrial Cancer and the Molecular Pathways Associated With Pathogenesis and Cancer Progression

Abstract

AT-rich interaction domain 1A gene (ARID1A) encodes for a subunit of the switch/sucrose non-fermentable (SWI/SNF) complex, a chromatin remodeling complex, and it has been implicated in the pathogenesis of various cancer types. In this review, we discuss how ARID1A is linked to endometrial cancer and what molecular pathways are affected by mutation or inhibition of ARID1A. We also discuss the potential use of ARID1A not only as a prognostic biomarker, but also as a target for therapeutic interventions. The dynamic modification of chromatin structure in a temporal-and spatial-specific manner determines cell fate by regulating expression levels of specific genes. The complexity of this process is further highlighted when considering all the endogenous and exogenous signals received by each cell during development and throughout its life. Numerous molecules (proteins and RNA) and macromolecular complexes are responsible for the organization of nucleosomes (Figure 1), epigenetic modifications, the dynamic change between the 'relaxed' or 'tight' conformation of chromatin (euchromatin and heterochromatin, respectively) and the accessibility of gene promoters determining cellular activities such as gene transcription, DNA repair and cell differentiation. Thus, disruption of normal chromatin remodeling impairs cellular development and homeostasis, and it has been associated extensively with tumorigenesis [reviewed in (1)]. The switch/sucrose non-fermentable (SWI/SNF) complex is a nucleosome-remodeling factor found in both eukaryotes and prokaryotes. It is involved in gene expression through transcriptional regulation and plays a pivotal role in carcinogenesis (2). This complex changes the DNA conformation in nucleosomes, allowing recruitment of transcription factors or other complexes responsible for DNA repair, replication and proliferation. Thus, when the SWI/SNF complex is disrupted, aberrant cell cycling is observed, as well as a loss of control of proliferation (3). SWI/SNF is a multi-subunit complex and many of its subunits, such AT-rich interaction domain 1A (ARID1A), ARID1B, SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2 (SMARCA2) and SMARCA4 (Figure 2), have been incriminated as driving mutations in various cancer types due to the high mutation frequencies observed (4). In particular, when considering human primary cancer cases with mutations in the SWI/SNF complex, most of the mutations seen are encountered in the gene encoding ARID1A (5-7). ARID1A and ARID1B genes encode DNA-targeting subunits, while SMARCA2 and SMARCA4 encode ATPase enzymes. The mutation frequency of these subunits in different cancer types seems to be tumor type-specific indicating that there is probably differential participation of the complex in gene regulation in different tissues (4). Loss of ARID1A has been shown in numerous human malignancies, such as uterine endometrioid carcinoma (8-10), ovarian endometrioid carcinoma (11), gastric cancer (12, 13), esophageal adenocarcinoma (14), pan...

Endometrial Cancer Incidence in Endometriosis and Adenomyosis

“…Furthermore, the process of epithelial-to-mesenchymal transition (EMT) seems to be crucial in the development of adenomyosis but also plays an important role in carcinogenesis [ 31 , 32 ]. Several studies have shown that changes in genes like AT-rich interactive domain-containing protein 1A (ARID1A), PTEN, KRAS, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) and Serine/threonine-protein phosphatase 2A 65 kDa regulatory subunit A alpha isoform (PPP2R1A) are present in women with endometriosis, but these are also known cancer-driving mutations involved in endometrial cancer carcinogenesis [ 33 , 34 ]. However, cancer-associated mutations were also found in endometriotic lesions without concurrent cancer, in particular in deep infiltrating lesions which are rarely associated with cancer development [ 35 ].…”

A Review of the Clinical Characteristics and Novel Molecular Subtypes of Endometrioid Ovarian Cancer

“…By comparing the mutant spectra of EOVC and EC (Table 2), many shared mutant genes have been identified: ARID1A, TP53, PTEN, PIK3CA, KRAS, CTNNB1, MMR, POLE, among others (51). However, the frequency of mutation of these genes appears to vary depending on different microenvironmental effects (50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60).…”

“…Summary of most common molecular alterations in EOVC and EEC(50)(51)(52)(53)(54)(55)(56)(57)(58)(59)(60).…”

Prognosis Stratification Tools in Early-Stage Endometrial Cancer: Could We Improve Their Accuracy?

“…We had almost no HER2 overexpression, so no correlations with the prognosis could be established [29]. Loss of ARID1A has been linked to shorter progression-free survival in EC, and loss of PTEN might be a good prognostic factor [30,31]. Our results are similar in terms of the positive proportion of cases for both biomarkers, but we did not nd any statistical signi cance related to survival.…”