Clinicopathologic and prognostic relevance of ARID1A protein loss in colorectal cancer

Xiao, Wei; Wang, De Shen; Xi, Shao Yan; Wu, Wen; Chen, Dong Liang; Zeng, Zhao Lei; Wang, Rui Yu; Huang, Ya Xin; Jin, Ying; Wang, Feng; Qiu, Miao Zhen; Luo, Hui; Zhang, Dong Sheng

doi:10.3748/wjg.v20.i48.18404

Cited by 44 publications

(58 citation statements)

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“…The ARID1A involvement in cell-cycle arrest shows that it significantly aids tumor repression, through the SWI/SNF complexes [17]. A wide range of cancer-gene mutations are detected by NGS and loss of function mutations in the ARID1A is detected repeatedly and frequently in various cancer types [13,21]. A recent study revealed that ARID1A knockdown in renal cells led to epithelial-mesenchymaltransition, highlighting its role in cell differentiation and tissue homeostasis [22].…”

Section: Introductionmentioning

confidence: 99%

Altered ARID1A expression in colorectal cancer

et al. 2020

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Background: ARID1A has been described as a tumor suppressor gene, participating in chromatin re-modeling, epithelial-mesenchymal-transition and many other cellular and molecular processes. It has been cited as a contribute in tumorigenesis. The role of ARID1A in CRC is not yet defined. Aim: To investigate the role of ARID1A methylation and CNV in its expression in CRC cell lines and to examine the relationship between ARID1A status with survival and clinicopathologic characteristics in patients with CRC. Methods: We used RT-PCR to determine both CNV and expression of ARID1A from six CRC cell lines. We used MSP to evaluate methylation of ARID1A. IHC was used to assess ARID1A protein expression. We also evaluated MSI and EMAST status in 18 paired CRC and adjacent normal tissues. 5AzadC was used to assess effect of DNA demethylation on ARID1A expression. Statistical analysis was performed to establish correlations between ARID1A expression and other parameters. Results: Among the 18 CRC tumors studied, 7 (38.8%) and 5 tumors (27.7%) showed no or low ARID1A expression, respectively. We observed no significant difference in ARID1A expression for overall patient survival, and no difference between clinicopathological parameters including MSI and EMAST. However, lymphatic invasion was more pronounced in the low/no ARID1A expression group when compared to moderate and high expression group (33% VS. 16.6% respectively. ARID1A promoter methylation was observed in 4/6 (66%) cell lines and correlated with ARID1A mRNA expression level ranging from very low in SW48, to more pronounced in HCT116 and HT-29/219. Treatment with the methyltransferase inhibitor 5-Azacytidine (5-aza) resulted in a 25.4-fold and 6.1-fold increase in ARID1A mRNA expression in SW48 and SW742 cells, respectively, while there was no change in SW480 and LS180 cells. No ARID1A CNV was observed in the CRC cell lines. Conclusion: ARID1A expression is downregulated in CRC tissues which correlates with it being a tumor suppressor protein. This finding confirms ARID1A loss of expression in CRC development. Our in-vitro results suggest high methylation status associates with reduced ARID1A expression and contributes to CRC tumorigenesis. However, there was no significant association between ARID1A loss of expression and clinicopathological characteristics. Future in-vivo analysis is warranted to further establish ARID1A role in colorectal neoplastic transformation.

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Section: Introductionmentioning

confidence: 99%

Altered ARID1A expression in colorectal cancer

et al. 2020

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“…6.2%-10.9% [34,48] ARID1A protein loss, due to mutations, is associated with the late TNM stage, distant metastasis, and poor pathologic differentiation in CRC patients [49] Retrospective Cohorts…”

Section: Arid1amentioning

confidence: 99%

“…Stage IV patients with ARID1A protein loss in primary tumors had longer survival compared to those with ARID1A positive tumors [49] CRC cell lines with mutated ARID1A are are selectively sensitized to ionizing radiation after knockdown of its other subunit, ARID1B [51].…”

Section: Arid1amentioning

confidence: 99%

“…ARID1A mutations and loss of its expression were observed in ovarian clear cell cancer [118], endometrioid cancer [119], breast cancer [120], Burkitt lymphoma [121], and lung cancer [122]. However, the investigation of this gene in the CRC is limited, and the mechanism by which the inactivation of the gene involved in tumorigenesis is not clearly understood [49].…”

Section: Arid1a Mutationsmentioning

confidence: 99%

“…Remarkably, the loss of ARID1A protein expression in CRC patients was significantly associated with poorly differentiated grade and advanced tumor depth [123], suggesting the loss of ARID1A protein expression as a predictive marker for poor prognosis CRC. However, some conflicting data exist, according to which the loss of ARID1A by immunohistochemistry was higher in primary CRCs with a frequency of 25.8% [49]. A higher prevalence of ARID1A mutation was observed in 18 out of 46 (39%) microsatellite instable (MSI) CRC, with almost half of them harboring the hotspot mutation c.5548delG7, indicating this mutation may play a role in MSI CRC [124].…”

Section: Arid1a Mutationsmentioning

confidence: 99%

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Actionable Potentials of Less Frequently Mutated Genes in Colorectal Cancer and Their Roles in Precision Medicine

et al. 2020

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Global statistics have placed colorectal cancer (CRC) as the third most frequently diagnosed cancer and the fourth principal cause of cancer-related deaths worldwide. Improving survival for CRC is as important as early detection. Personalized medicine is important in maximizing an individual’s treatment success and minimizing the risk of adverse reactions. Approaches in achieving personalized therapy in CRC have included analyses of specific genes with its clinical implications. Tumour genotyping via next-generation sequencing has become a standard practice to guide clinicians into predicting tumor behaviour, disease prognosis, and treatment response. Nevertheless, better prognostic markers are necessary to further stratify patients for personalized treatment plans. The discovery of new markers remains indispensable in providing the most effective chemotherapy in order to improve the outcomes of treatment and survival in CRC patients. This review aims to compile and discuss newly discovered, less frequently mutated genes in CRC. We also discuss how these mutations are being used to assist therapeutic decisions and their potential prospective clinical utilities. In addition, we will summarize the importance of profiling the large genomic rearrangements, gene amplification, and large deletions and how these alterations may assist in determining the best treatment option for CRC patients.

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SWI / SNF Chromatin Remodelling and Human Cancer

Reisman

Thompson

Marquez-Vilendrer

et al. 2016

Encyclopedia of Life Sciences

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Brahma (BRM) and Brahma‐related gene 1 (BRG1) are two mutually exclusively catalytic subunits of the switch in mating type/sucrose nonfermenting complex. These two key anticancer proteins are frequently targeted and silenced during cancer development. The anticancer function of BRM can be abrogated when it becomes acetylated or when it is epigenetically silenced. Central to BRM silencing is the presence of two inherited insertional polymorphisms within the BRM promoter that are statistically linked to cancer risk. Both BRM acetylation and silencing can be reversed by a number of compound families and might be important to how flavonoids and NSAIDS inhibit cancer. While BRG1 is very frequently mutated in most human cancers, it is more commonly inactivated by aberrant splicing and by an AKT‐pathway‐mediated‐translation block. While BRG1 and BRM are tied to deoxyribonucleic acid repair, growth control, differentiation, development, as well as epithelial–mesenchymal transition and are estimated to regulate 4–8% of the human genome, the inactivation of either protein is only modestly tumourigenic. This occurs in part because BRG1 and BRM are functionally redundant, which blunts the tumourigenic effect when only one gene is aberrantly silenced. Further insights into the mechanisms that regulate these genes may lead to novel therapeutic strategies that may reverse the silencing of these two important anticancer genes. Key Concepts Reversal of the epigenetic silencing of a gene may serve as a basis for drug therapy. Anticancer genes are epigenetically regulated by insertional polymorphisms. The functional redundancy of BRG1 and BRM thwarts cancer development. Post‐translational modification of BRM and BRG1 alters the cellular roles of these proteins from growth inhibitors to growth promoters. The loss of cofactors (i.e. BRG1 and/or BRM) for RB‐mediated‐growth inhibition could preclude the function of CDK inhibitors used clinically. Specific SWI/SNF subunits are commonly mutated and inactivated in specific cancer types. Diminished SWI/SNF activity, but not the complete abrogation of function, is tumourigenic.

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Clinicopathologic and prognostic relevance of ARID1A protein loss in colorectal cancer

Abstract: ARID1A protein loss is associated with clinicopathologic characteristics in colorectal cancer patients and with survival in stage IV patients.

Cited by 44 publications

References 45 publications

Altered ARID1A expression in colorectal cancer

Altered ARID1A expression in colorectal cancer

Actionable Potentials of Less Frequently Mutated Genes in Colorectal Cancer and Their Roles in Precision Medicine

SWI / SNF Chromatin Remodelling and Human Cancer

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