Prognostic and Clinicopathological Significance of ARID1A in Endometrium‐Related Gynecological Cancers: A Meta‐Analysis

Liu, Guangquan; Xu, Pengfei; Fu, Ziyi; Hua, Xiangdong; Liu, Xiaoguang; Li, Wenqu; Zhang, Mi; Wu, Jiacong; Wen, Juan; Xu, Juan; Jia, Xuemei

doi:10.1002/jcb.26109

Cited by 20 publications

(20 citation statements)

References 32 publications

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“…Pathological assessment was not performed on iPAD mice at weeks 16 and 20 due to cancer-related morbidity and mortality. All iPAD control mice were alive and active at both16 and 20 weeks. Each circle represents an individual uterine sample.…”

mentioning

confidence: 99%

“…Complete loss of ARID1A expression or clonal ARID1A mutation is rare in atypical endometrial hyperplasia while up to one-third of endometrioid carcinomas lose ARID1A expression or harbor somatic ARID1A mutations. Moreover, loss of ARID1A expression in endometrial biopsy or curettage is associated with a significantly increased risk and FIGO stages of uterine endometrioid carcinoma in subsequent hysterectomies 16 . These above findings suggest that ARID1A participates in progression rather than initiation of endometrioid carcinoma of the uterus.…”

mentioning

confidence: 99%

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Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming

et al. 2020

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Somatic inactivating mutations of ARID1A, a SWI/SNF chromatin remodeling gene, are prevalent in human endometrium-related malignancies. To elucidate the mechanisms underlying how ARID1A deleterious mutation contributes to tumorigenesis, we establish genetically engineered murine models with Arid1a and/or Pten conditional deletion in the endometrium. Transcriptomic analyses on endometrial cancers and precursors derived from these mouse models show a close resemblance to human uterine endometrioid carcinomas. We identify transcriptional networks that are controlled by Arid1a and have an impact on endometrial tumor development. To verify findings from the murine models, we analyze ARID1A WT and ARID1A KO human endometrial epithelial cells. Using a system biology approach and functional studies, we demonstrate that ARID1A-deficiency lead to loss of TGFβ tumor suppressive function and that inactivation of ARID1A/TGF-β axis promotes migration and invasion of PTEN-deleted endometrial tumor cells. These findings provide molecular insights into how ARID1A inactivation accelerates endometrial tumor progression and dissemination, the major causes of cancer mortality.

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confidence: 99%

mentioning

confidence: 99%

Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming

et al. 2020

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“…We next sought to further interrogate the spatial locations of key immune subpopulations known to promote an immunosuppressive environment [41][42][43][44], including comparison of immune cell location amongst the tumour cells relative to the stroma. We therefore investigated the spatial locations of tumour-associated macrophages (TAMs) by assessing CD68 + cells, activated TAMs (PD-L1 + CD68 + cells), regulatory T cells (FOXP3 + CD4 + cells and activated regulatory T cells; PD-L1 + FOXP3 + CD4 + triple positive cells [45]), stratifying into tumoral and stromal locations.…”

Section: Spatial Distribution Of Immunosuppressive Immune Subpopulations Is Associated With Risk Status and Arid1a Mutational Status In Omentioning

confidence: 99%

Quantitative Assessment and Prognostic Associations of the Immune Landscape in Ovarian Clear Cell Carcinoma

Khalique

Nash

Mansfield

et al. 2021

Cancers

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Ovarian clear cell carcinoma (OCCC) is a rare subtype of epithelial ovarian cancer characterised by a high frequency of loss-of-function ARID1A mutations and a poor response to chemotherapy. Despite their generally low mutational burden, an intratumoural T cell response has been reported in a subset of OCCC, with ARID1A purported to be a biomarker for the response to the immune checkpoint blockade independent of micro-satellite instability (MSI). However, assessment of the different immune cell types and spatial distribution specifically within OCCC patients has not been described to date. Here, we characterised the immune landscape of OCCC by profiling a cohort of 33 microsatellite stable OCCCs at the genomic, gene expression and histological level using targeted sequencing, gene expression profiling using the NanoString targeted immune panel, and multiplex immunofluorescence to assess the spatial distribution and abundance of immune cell populations at the protein level. Analysis of these tumours and subsequent independent validation identified an immune-related gene expression signature associated with risk of recurrence of OCCC. Whilst histological quantification of tumour-infiltrating lymphocytes (TIL, Salgado scoring) showed no association with the risk of recurrence or ARID1A mutational status, the characterisation of TILs via multiplexed immunofluorescence identified spatial differences in immunosuppressive cell populations in OCCC. Tumour-associated macrophages (TAM) and regulatory T cells were excluded from the vicinity of tumour cells in low-risk patients, suggesting that high-risk patients have a more immunosuppressive microenvironment. We also found that TAMs and cytotoxic T cells were also excluded from the vicinity of tumour cells in ARID1A-mutated OCCCs compared to ARID1A wild-type tumours, suggesting that the exclusion of these immune effectors could determine the host response of ARID1A-mutant OCCCs to therapy. Overall, our study has provided new insights into the immune landscape and prognostic associations in OCCC and suggest that tailored immunotherapeutic approaches may be warranted for different subgroups of OCCC patients.

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“…ARID1A has also been used as a prognostic marker in endometrial cancer. A significant association of reduced ARID1A expression has been found with shorter progression-free survival in patients suffering from endometrium-related cancer and, especially from ovarian clear-cell carcinoma, as well as with higher FIGO stage of both endometrial and ovarian cancer (45). Furthermore, the very rare occurrence of ARID1A mutations in complex atypical hyperplasia cases compared to endometrioid endometrial carcinoma (9,46), in conjunction with evidence linking ARID1A to tumor initiation and progression suggest that it might play a significant role in the transition from complex atypical hyperplasia to carcinoma through somatic inactivating mutations (47).…”

Section: Endometrial Cancer and Arid1amentioning

confidence: 99%

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

Toumpeki

Liberis²,

Tsirkas

et al. 2019

In Vivo

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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...

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Prognostic and Clinicopathological Significance of ARID1A in Endometrium‐Related Gynecological Cancers: A Meta‐Analysis

Cited by 20 publications

References 32 publications

Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming

Inactivation of Arid1a in the endometrium is associated with endometrioid tumorigenesis through transcriptional reprogramming

Quantitative Assessment and Prognostic Associations of the Immune Landscape in Ovarian Clear Cell Carcinoma

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

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