Comprehensive Immunohistochemical Study of the SWI/SNF Complex Expression Status in Gastric Cancer Reveals an Adverse Prognosis of SWI/SNF Deficiency in Genomically Stable Gastric Carcinomas

Glückstein, Marie-Isabelle; Dintner, Sebastian; Arndt, Tim Tobias; Vlasenko, Dmytro; Schenkirsch, Gerhard; Agaimy, Abbas; Müller, Gernot; Märkl, Bruno; Grosser, Bianca

doi:10.3390/cancers13153894

Cited by 13 publications

(10 citation statements)

References 52 publications

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“…Some studies on gastric adenocarcinoma found SWI/SNF complex abnormalities to be an independent prognostic factor for OS in the GS subtype 28,29 . Interestingly, ARID1A negative expression exhibited worse survival in the EBV subtype, 29 which was inconsistent with our present study, possibly due to different ARID1A classification methods or bias caused by too few patients in the subgroup.…”

Section: Discussioncontrasting

confidence: 99%

Prognostic and immune infiltration significance of ARID1A in TCGA molecular subtypes of gastric adenocarcinoma

Zhang

Sun

et al. 2023

Cancer Medicine

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BackgroundAT‐rich interaction domain 1A (ARID1A) is an essential subunit of the switch/sucrose non‐fermentable chromatin remodeling complex and is considered to be a tumor suppressor. The Cancer Genome Atlas (TCGA) molecular classification has deepened our understanding of gastric cancer at the molecular level. This study explored the significance of ARID1A expression in TCGA subtypes of gastric adenocarcinoma.MethodsWe collected 1248 postoperative patients with gastric adenocarcinoma, constructed tissue microarrays, performed immunohistochemistry for ARID1A, and obtained correlations between ARID1A and clinicopathological variables. We then carried out the prognostic analysis of ARID1A in TCGA subtypes. Finally, we screened patients by random sampling and propensity score matching method and performed multiplex immunofluorescence to explore the effects of ARID1A on CD4, CD8, and PD‐L1 expression in TCGA subtypes.ResultsSeven variables independently associated with ARID1A were screened out: mismatch repair proteins, PD‐L1, T stage, differentiation status, p53, E‐cadherin, and EBER. The independent prognostic variables in the genomically stable (GS) subtype were N stage, M stage, T stage, chemotherapy, size, and ARID1A. PD‐L1 expression was higher in the ARID1A negative group than in the ARID1A positive group in all TCGA subgroups. CD4 showed higher expression in the ARID1A negative group in most subtypes, while CD8 did not show the difference in most subtypes. When ARID1A was negative, PD‐L1 expression was positively correlated with CD4/CD8 expression; while when ARID1A was positive, this correlation disappeared.ConclusionsThe negative expression of ARID1A occurred more frequently in the Epstein–Barr virus and microsatellite instability subtypes and was an independent adverse prognostic factor in the GS subtype. In the TCGA subtypes, ARID1A negative expression caused increased CD4 and PD‐L1 expression, whereas CD8 expression appeared independent of ARID1A. The expression of CD4/CD8 induced by ARID1A negativity was accompanied by an increase in PD‐L1 expression.

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Section: Discussioncontrasting

confidence: 99%

Prognostic and immune infiltration significance of ARID1A in TCGA molecular subtypes of gastric adenocarcinoma

Zhang

Sun

et al. 2023

Cancer Medicine

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“…highest loss ratio (12/21, 57.14%), followed by ARID1A (5/21, 23.81%) and SMARCA4 (3/21, 14.29%). The loss ratio of the above three subunits in undifferentiated/ dedifferentiated gastric carcinoma was significantly higher than that in ordinary gastric adenocarcinoma [8,9], suggesting a correlation between the differentiation status and the loss of SWI/SNF complex subunits. Our current study also showed the CSC phenotype appeared more frequently in the SWI/SNF complex deficient group (Table 4).…”

Section: Discussionmentioning

confidence: 89%

“…Many studies on the loss of SWI/SNF complex subunits in conventional gastric adenocarcinoma have been reported [8,9]. Conversely, in undifferentiated/dedifferentiated gastric carcinoma, studies related to SWI/SNF complex are limited due to the rarity of cases.…”

Section: Introductionmentioning

confidence: 99%

Clinicopathological and prognostic significance of SWI/SNF complex subunits in undifferentiated gastric carcinoma

Zhang

Sun

et al. 2022

World J Surg Onc

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Background The switch/sucrose nonfermentable (SWI/SNF) complex is an evolutionarily conserved chromatin remodeling complex that displays dysfunction in many tumors, especially undifferentiated carcinoma. Cancer stem cells (CSC), a special type of undifferentiated cancer cells with stem cell-like properties, play an essential role in tumor cell proliferation, invasion, and metastasis. In undifferentiated gastric carcinomas, the association of SWI/SNF complexes with clinicopathological features, CSC phenotype, and the prognosis is not fully understood. Methods We collected a cohort of 21 patients with undifferentiated/dedifferentiated gastric carcinoma. We next performed immunohistochemistry staining for the five subunits of the SWI/SNF complex (ARID1A, ARID1B, SMARCA2, SMARCA4, and SMARCB1), and four mismatch repair proteins (MLH1, PMS2, MSH2, and MSH6), as well as other markers such as p53, PD-L1, and cancer stem cell (CSC) markers (SOX2, SALL4). Then, we investigated the correlation of SWI/SNF complex subunits with clinicopathological characters and performed prognostic analysis. Results We observed SMARCA2 loss in 12 cases (57.14%), followed by ARID1A (5 cases, 23.81%) and SMARCA4 (3 cases, 14.29%). Fourteen cases (66.67%) lost any one of the SWI/SNF complex subunits, including 3 cases with SMARCA2 and ARID1A co-loss, and 3 cases with SMARCA2 and SMARCA4 co-loss. Correlation analysis revealed that the CSC phenotype occurred more frequently in the SWI/SNF complex deficient group (P = 0.0158). Survival analysis revealed that SWI/WNF complex deficiency, undifferentiated status, CSC phenotype, and the loss of SMARCA2 and SMARCA4 resulted in worse survival. Univariate and multivariate Cox regression analyses screened out three independent factors associated with worse prognosis: undifferentiated status, SWI/SNF complex deficiency, and lymph node metastasis. Conclusions The SWI/SNF complex deficiency was more likely to result in a CSC phenotype and worse survival and was an independent prognostic factor in undifferentiated/dedifferentiated gastric carcinoma.

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“…This can be accomplished via an increase in the accessibility to transcription factors, as the SWI/SNF complex has the ability to mobilize and shift nucleosomes 59,60 . Multiple subunits of the SWI/SNF complex have been associated with gastric cancer development [61][62][63][64] . Most notably, unbiased genome and exome sequencing studies have identified ARID1A, a gene encoding the DNA interacting subunit of the SWI/SNF complex 65 , as the second most frequently mutated gene after TP53 in GC 5,66,67 .…”

Section: Alterations In Chromatin Remodeling Complexes Play Functiona...mentioning

confidence: 99%

Chromatin and noncoding RNA-mediated mechanisms of gastric tumorigenesis

2023

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Gastric cancer (GC) is one of the most common and deadly cancers in the world. It is a multifactorial disease highly influenced by environmental factors, which include radiation, smoking, diet, and infectious pathogens. Accumulating evidence suggests that epigenetic regulators are frequently altered in GC, playing critical roles in gastric tumorigenesis. Epigenetic regulation involves DNA methylation, histone modification, and noncoding RNAs. While it is known that environmental factors cause widespread alterations in DNA methylation, promoting carcinogenesis, the chromatin- and noncoding RNA-mediated mechanisms of gastric tumorigenesis are still poorly understood. In this review, we focus on discussing recent discoveries addressing the roles of histone modifiers and noncoding RNAs and the mechanisms of their interactions in gastric tumorigenesis. A better understanding of epigenetic regulation would likely facilitate the development of novel therapeutic approaches targeting specific epigenetic regulators in GC.

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Comprehensive Immunohistochemical Study of the SWI/SNF Complex Expression Status in Gastric Cancer Reveals an Adverse Prognosis of SWI/SNF Deficiency in Genomically Stable Gastric Carcinomas

Cited by 13 publications

References 52 publications

Prognostic and immune infiltration significance of ARID1A in TCGA molecular subtypes of gastric adenocarcinoma

Prognostic and immune infiltration significance of ARID1A in TCGA molecular subtypes of gastric adenocarcinoma

Clinicopathological and prognostic significance of SWI/SNF complex subunits in undifferentiated gastric carcinoma

Chromatin and noncoding RNA-mediated mechanisms of gastric tumorigenesis

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