The Role of ARID1A in Tumors: Tumor Initiation or Tumor Suppression?

Xu, Shouying; Tang, Chao

doi:10.3389/fonc.2021.745187

Cited by 38 publications

(44 citation statements)

References 204 publications

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“…1 ). ARID1A is also known as Brahma-related associated factor 250a (BAF250a), SWI/SNF-related matrix-associated actin-dependent regulators of chromatin factor 1 (SMARCF1), B120, C1orf4, Osa1, or p270 [ 9 , 10 ]. The gene encoding ARID1A is located on chromosome 1p36.11.…”

Section: Arid1a and Chromatin Remodeling Mechanismmentioning

confidence: 99%

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Mandal

Wang

et al. 2022

J Biomed Sci

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Chromatin remodeling is an essential cellular process for organizing chromatin structure into either open or close configuration at specific chromatin locations by orchestrating and modifying histone complexes. This task is responsible for fundamental cell physiology including transcription, DNA replication, methylation, and damage repair. Aberrations in this activity have emerged as epigenomic mechanisms in cancer development that increase tumor clonal fitness and adaptability amidst various selection pressures. Inactivating mutations in AT-rich interaction domain 1A (ARID1A), a gene encoding a large nuclear protein member belonging to the SWI/SNF chromatin remodeling complex, result in its loss of expression. ARID1A is the most commonly mutated chromatin remodeler gene, exhibiting the highest mutation frequency in endometrium-related uterine and ovarian carcinomas. As a tumor suppressor gene, ARID1A is essential for regulating cell cycle, facilitating DNA damage repair, and controlling expression of genes that are essential for maintaining cellular differentiation and homeostasis in non-transformed cells. Thus, ARID1A deficiency due to somatic mutations propels tumor progression and dissemination. The recent success of PARP inhibitors in treating homologous recombination DNA repair-deficient tumors has engendered keen interest in developing synthetic lethality-based therapeutic strategies for ARID1A-mutated neoplasms. In this review, we summarize recent advances in understanding the biology of ARID1A in cancer development, with special emphasis on its roles in DNA damage repair. We also discuss strategies to harness synthetic lethal mechanisms for future therapeutics against ARID1A-mutated cancers.

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Section: Arid1a and Chromatin Remodeling Mechanismmentioning

confidence: 99%

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Mandal

Wang

et al. 2022

J Biomed Sci

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“…It has been previously demonstrated that mutations in ARID1A are associated with a worse prognosis, mainly in the No Specific Molecular Profile (NSMP) group [6]. As regarding possible therapy associated with ARID1A alterations, multiple therapeutic targets (e.g., PARP, EZH2, PIK3CA) have been extensively studied according to the mutational status of ARID1A [38]. The ARID1A loss has been associated with a higher sensitivity to elesclomol (an HSP-90 inhibitor with proapoptotic activity), in endometrial cancer cell lines [39].…”

Section: Discussionmentioning

confidence: 99%

Relevance of ARID1A Mutations in Endometrial Carcinomas

et al. 2022

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Since the Cancer Genome Atlas (TCGA) project identified four distinct groups based on molecular alterations, mutation analyses have been integrated into the characterization of endometrial carcinomas (ECs). ARID1A seems to be the subunit more involved in the loss of function of the SWI/SNF complex in ECs. The aim of this study is to define the relevance of ARID1A alterations in a cohort of EC, studying the possible associations between DNA mutation (genomic level), RNA expression (transcriptomic level), and protein expression (proteomic level). A total of 50 endometrial carcinomas were characterized for ARID1A mutations (using targeted DNA next-generation sequencing—NGS), ARID1A gene expression (using RNAseq and qRT-PCR), and ARID1A protein expression (using immunohistochemistry—IHC). Moreover, we have investigated if ARID1A mutations may alter the protein structure, using the Protein Data Bank sequence. We found a good correlation between ARID1A mutations and protein immunostaining, even if we did not find statistically significant differences in the ARID1A expression levels. In conclusion, our data demonstrated that the molecular characterization of ARID1A should be associated with IHC analysis, mainly in those cases harboring “novel” ARID1A mutations or in those alterations with “uncertain” pathogenic significance.

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“…In clinical practice, it is difficult to recover from the abnormal deletion of gene products, but abnormal SWI/SNF subunits often co-occur with abnormalities of other molecular signaling pathways. The use of specific synthetic lethal relationships is an effective approach to its treatment and has now become a hot field of precision therapy ( 27 ). This study showed that PBRM1 deletion/mutation is closely related to PIK3CA mutation and that KEGG signaling pathways enriched for PBRM1 expression loss include lysine degradation, antigen processing and presentation, the Notch signaling pathway and phagosome-related genes in GACs.…”

Section: Discussionmentioning

confidence: 99%

Clinicopathological Significance, Related Molecular Changes and Tumor Immune Response Analysis of the Abnormal SWI/SNF Complex Subunit PBRM1 in Gastric Adenocarcinoma

Zhou¹,

Huang²,

Yang³

et al. 2022

Pathol. Oncol. Res.

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Background: PBRM1 gene abnormalities were recently found to play a role in tumor development and tumor immune activity. This article will explore the clinicopathological and molecular changes and tumor immune activity of the abnormal SWI/SNF complex subunit PBRM1 in gastric adenocarcinoma (GAC) and its significance.Methods: The cBioPortal, LinkedOmics and TISIDB datasets were used to analyze the abnormality of the PBRM1 gene in GAC and its relationship with prognosis, related molecular changes and tumor-infiltrating lymphocytes (TILs). In addition, 198 GAC cases were collected to further study the relationship between the loss/attenuation of PBRM1 expression and clinicopathology, prognosis, microsatellite stability, PD-L1 expression and TIL in GAC. DNA whole-exome sequencing was performed on 7 cases of gastric cancer with loss of PBRM1 expression.Results: The cBioPortal data showed that PBRM1 deletion/mutation accounted for 7.32% of GAC and was significantly associated with several molecular changes, such as molecular subtypes of GAC. The LinkedOmics dataset showed that PBRM1 mutation and its promoter DNA methylation showed lower PBRM1 mRNA expression, and PBRM1 mutation cases showed significantly higher mRNA expression of PD-L1 (CD274). TISIDB data showed that PBRM1 abnormalities were significantly positively associated with multiple TILs. In our group of 198 cases, the loss/attenuation of PBRM1 expression was significantly positively correlated with intra-tumoral tumor infiltrating lymphocytes (iTILs) and deficient MMR and PD-L1 expression. Kaplan–Meier survival analysis showed that the overall survival of GAC patients with loss/attenuation of PBRM1 expression was significantly better (p = 0.023). iTIL was an independent prognostic factor of GAC. Loss of PBRM1 expression often co-occurs with mutations in other SWI/SNF complex subunit genes, and there are some repetitive KEGG signaling changes.Conclusion: Abnormality of the PBRM1 gene may be related to the occurrence of some GACs and can affect tumor immune activity, thereby affecting clinicopathology and prognosis. It may be a potentially effective predictive marker for immunotherapy and a novel therapeutic approach associated with synthetic lethality.

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The Role of ARID1A in Tumors: Tumor Initiation or Tumor Suppression?

Cited by 38 publications

References 204 publications

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Treating ARID1A mutated cancers by harnessing synthetic lethality and DNA damage response

Relevance of ARID1A Mutations in Endometrial Carcinomas

Clinicopathological Significance, Related Molecular Changes and Tumor Immune Response Analysis of the Abnormal SWI/SNF Complex Subunit PBRM1 in Gastric Adenocarcinoma

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