Tumor progression by epithelial-mesenchymal transition in ARID1A- and SMARCA4-aberrant solid-type poorly differentiated gastric adenocarcinoma

Sasaki, Taisuke; Kohashi, Kenichi; Kawatoko, Shinichiro; Ihara, Eikichi; Oki, Eiji; Nakamura, Masafumi; Ogawa, Yoshihiro; Oda, Yoshinao

doi:10.1007/s00428-021-03261-9

Cited by 7 publications

(6 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, E‐cadherin expression was downregulated or absent when ARID1A was silenced, 23 and the loss of E‐cadherin led to epithelial‐mesenchymal transition (EMT), further increasing tumor aggressiveness. 24 ARID1A was inversely correlated with TP53 , and simultaneous mutations in ARID1A and TP53 were rarely observed in the same tumor. 14 , 19 , 25 In addition, the loss of ARID1A caused worse differentiation and deeper tumor invasion in gastric cancer.…”

Section: Discussionmentioning

confidence: 91%

“…Several other variables related to ARID1A observed in this study were also confirmed in previous studies. For example, E‐cadherin expression was downregulated or absent when ARID1A was silenced, 23 and the loss of E‐cadherin led to epithelial‐mesenchymal transition (EMT), further increasing tumor aggressiveness 24 . ARID1A was inversely correlated with TP53 , and simultaneous mutations in ARID1A and TP53 were rarely observed in the same tumor 14,19,25 .…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Zhang

Sun

et al. 2023

Cancer Medicine

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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

Zhang

Sun

et al. 2023

Cancer Medicine

View full text Add to dashboard Cite

show abstract

“…SMARCA4 mutations occurred in 8% (20/258) of gastric cancers in a TCGA analysis and 10% (5/50) of gastric cancers in Takeshima’s study ( 1 , 18 ). Loss of SMARCA4 is associated with adverse clinical characteristics ( 19 , 20 ). SMARCA4 (BRG1) deficiency occurs rarely in subsets of NECs, such as SCCOHT ( 8 ) and lung neuroendocrine carcinomas ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

“…Inactivation of SMARCA4 is more likely to occur in gastric cancer with a solid and undifferentiated morphology, presenting in large and locally advanced tumors ( 21 – 23 ). Aberrant SMARCA4 protein expression was reported to be frequently observed in 49% (25/51) of solid-type poorly differentiated adenocarcinomas and nonsolid-type poorly differentiated adenocarcinomas (7.5%, 3/40) ( 20 ). However, GI NEC with SMARCA4 deficiency has not been reported in the published English literature.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Gastrointestinal neuroendocrine carcinoma with SMARCA4 deficiency: a clinicopathological report of two rare cases

Zhou,

Fu,

Wang

2023

Front. Oncol.

View full text Add to dashboard Cite

BackgroundGastrointestinal neuroendocrine carcinoma (GI NEC) is a rare but highly malignant neoplasm with an aggressive clinical course. SMARCA4 is one of the subunits of the SWI/SNF chromatin remodeling complex. SMARCA4 deficiency can occur rarely in subsets of NECs. Reports of the clinicopathological features of GI NECs with SMARCA4 deficiency are limited.MethodsIn this study, we retrospectively reported two rare cases of GI NEC with SMARCA4 deficiency and described the clinicopathological, radiographic and histopathological features.ResultsCase 1 was a 43-year-old male with a stage cT3NxM1, IV tumor. Case 2 was a 64-year-old female with a stage cT4aN1M0, IIIA tumor. Both tumors presented as ulcerated masses with infiltration. Pathological examination indicated a solid architecture with poorly differentiated morphology, and complete loss of SMARCA4 (BRG1) was found. Immunohistochemical staining showed positivity for Syn, CgA and CD56. The Ki-67 index was 90% and 70%, respectively. None of the cases had mismatch repair (MMR) deficiency. Case 1 received treatment with chemotherapy and anti-PD-1 immunotherapy. He did not respond to treatment, and died 9 months later. Case 2 received neoadjuvant chemotherapy before surgical treatment, and the tumor showed TRG3 in response to neoadjuvant chemotherapy, chemotherapy and anti-PD-1 immunotherapy were continued after surgical resection. There was no evidence of disease for 10 months.ConclusionsGI NEC with SMARCA4 deficiency is a rare entity of gastric NEC. SMARCA4 may be a promising targetable and prognostic biomarker. BRG1 immunohistochemical staining could be performed for GI NECs. Further studies with a larger cohort will be needed.

show abstract

“…Monitoring tumor formation in NSCLC GEMMs of lung adenocarcinoma (KPS: Kras LSL-G12D/+ ; Trp53 lox/lox ; Smarca4 lox/lox ) revealed that regardless of the cell type in which the alleles were targeted (alveolar type II epithelial cells or club cells), Smarca4 loss led to increased metastasis 87 . In studies of both gastric cancer and pancreatic ductal adenocarcinoma (PDAC), analysis of patient samples and available cell lines revealed that loss of either Smarca4 or Arid1a led to increased metastasis and decreased CDH1 expression [88][89][90] . Furthermore, SMARCA4 loss in triple-negative breast cancer (TNBC) cell lines was associated with an increased mesenchymal signature, including increased expression of SNAIL, TWIST, and CDH2 and increased HIPPO pathway activity 91 .…”

Section: Expanding Landscape Of Epigenetic Dysregulation Underlying C...mentioning

confidence: 99%

Effect of chromatin modifiers on the plasticity and immunogenicity of small-cell lung cancer

2022

View full text Add to dashboard Cite

Tumor suppressor genes (TSGs) are often involved in maintaining homeostasis. Loss of tumor suppressor functions causes cellular plasticity that drives numerous types of cancer, including small-cell lung cancer (SCLC), an aggressive type of lung cancer. SCLC is largely driven by numerous loss-of-function mutations in TSGs, often in those encoding chromatin modifiers. These mutations present a therapeutic challenge because they are not directly actionable. Alternatively, understanding the resulting molecular changes may provide insight into tumor intervention strategies. We hypothesize that despite the heterogeneous genomic landscape in SCLC, the impacts of mutations in patient tumors are related to a few important pathways causing malignancy. Specifically, alterations in chromatin modifiers result in transcriptional dysregulation, driving mutant cells toward a highly plastic state that renders them immune evasive and highly metastatic. This review will highlight studies in which imbalance of chromatin modifiers with opposing functions led to loss of immune recognition markers, effectively masking tumor cells from the immune system. This review also discusses the role of chromatin modifiers in maintaining neuroendocrine characteristics and the role of aberrant transcriptional control in promoting epithelial-to-mesenchymal transition during tumor development and progression. While these pathways are thought to be disparate, we highlight that the pathways often share molecular drivers and mediators. Understanding the relationships among frequently altered chromatin modifiers will provide valuable insights into the molecular mechanisms of SCLC development and progression and therefore may reveal preventive and therapeutic vulnerabilities of SCLC and other cancers with similar mutations.

show abstract

Tumor progression by epithelial-mesenchymal transition in ARID1A- and SMARCA4-aberrant solid-type poorly differentiated gastric adenocarcinoma

Cited by 7 publications

References 32 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

Case Report: Gastrointestinal neuroendocrine carcinoma with SMARCA4 deficiency: a clinicopathological report of two rare cases

Effect of chromatin modifiers on the plasticity and immunogenicity of small-cell lung cancer

Contact Info

Product

Resources

About