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ARID1A expression in gastric adenocarcinoma: clinicopathological significance and correlation with DNA mismatch repair status.

ABSTRACT: To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables.The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and was significantly associated with an older age (68.6±9.2 vs 60.4±11.7, P<0.001), a female sex (55.3% vs 31.3%, P=0.004), an antral location (44.7% vs 25.7%, P=0.021), and a differentiated histology (57.9% vs 39.7%, P=0.023). Abnormal ARID1A expression, including reduced or loss of ARID1A expression, was observed in 109 cases (22.3%) and was significantly correlated with lymphatic invasion (80.7% vs 69.5%, P=0.022) and lymph node metastasis (83.5% vs 73.7%, P=0.042). The tumors with abnormal ARID1A expression more frequently indicated MMR deficiency (47.4% vs 20.2%, P<0.001). A multivariate analysis identified abnormal ARID1A expression as an independent poor prognostic factor (HR=1.36, 95%CI: 1.01-1.84; P=0.040).Our observations suggest that the AIRD1A inactivation is associated with lymphatic invasion, lymph node metastasis, poor prognosis, and MMR deficiency in gastric adenocarcinomas.

SUBMITTER: Inada R

PROVIDER: S-EPMC4326154 | biostudies-literature | 2015 Feb

REPOSITORIES: biostudies-literature

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ARID1A expression in gastric adenocarcinoma: clinicopathological significance and correlation with DNA mismatch repair status.

Inada Ryo R Sekine Shigeki S Taniguchi Hirokazu H Tsuda Hitoshi H Katai Hitoshi H Fujiwara Toshiyoshi T Kushima Ryoji R

World journal of gastroenterology 20150201 7

<h4>Aim</h4>To analyze the mismatch repair (MMR) status and the ARID1A expression as well as their clinicopathological significance in gastric adenocarcinomas.<h4>Methods</h4>We examined the expressions of MMR proteins and ARID1A by immunohistochemistry in consecutive 489 primary gastric adenocarcinomas. The results were further correlated with clinicopathological variables.<h4>Results</h4>The loss of any MMR protein expression, indicative of MMR deficiency, was observed in 38 cases (7.8%) and w ...[more]

PMID: 25717252

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Project description: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.

Project description:BackgroundIt has recently been reported that mismatch repair (MMR) status and microsatellite instability (MSI) status in gastroesophageal carcinomas predict surgical, chemotherapeutic and immunotherapeutic outcomes; however, there is extensive variability in the reported incidence and clinical implications of MMR/MSI status in gastroesophaegal adenocarcinomas. We characterized a Canadian surgical patient cohort with respect to MMR status, clinicopathologic correlates and anatomic tumour location.MethodsWe investigated MMR and BRAF V600E status of gastroesophaegal adenocarcinomas in patients who underwent gastrectomy or esophagectomy with extended (D2) lymphadenectomy at a single centre between 2011 and 2019. We correlated patterns of MMR expression in the overall cohort and in anatomic location-defined subgroups with treatment response and overall survival using multivariate analysis.ResultsIn all, 226 cases of gastroesophaegal adenocarcinoma (63 esophageal, 98 gastroesophageal junctional and 65 gastric) were included. The MMR-deficient (dMMR) immunophenotype was found in 28 tumours (12.3%) (15 junctional [15.3%], 13 gastric [20.0%] and none of the esophageal). The majority (25 [89%]) of dMMR cases showed MLH1/PMS2 loss without concurrent BRAF V600E mutation. Two MSH2/ MSH6-deficient gastric tumours and 1 MSH6-deficient junctional tumour were detected. The pathologic response to preoperative chemotherapy was comparable in the dMMR and MMR-proficient (pMMR) cohorts. However, dMMR status was associated with significantly longer median overall survival than pMMR status (5.8 yr v. 2.4 yr, hazard ratio [HR] 1.91, 95% confidence interval [CI] 1.06-3.46), particularly in junctional tumours (4.6 yr v. 1.9 yr, HR 2.97, 95% CI 1.27-6.94).ConclusionOur study shows that MMR status has at least prognostic value, which supports the need for biomarker testing in gastroesophageal adenocarcinomas, including junctional adenocarcinomas. This highlights the clinical significance of determining the MMR status in all adenocarcinomas of the upper gastrointestinal tract. Response to induction chemotherapy, however, was not influenced by MMR status.

Dataset Information

ARID1A expression in gastric adenocarcinoma: clinicopathological significance and correlation with DNA mismatch repair status.

Publications

ARID1A expression in gastric adenocarcinoma: clinicopathological significance and correlation with DNA mismatch repair status.

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