Abstract
The tumor suppressor gene AT-rich interactive domain 1A (ARID1A) and systemic inflammatory response (SIR) have been reported to be related to the sensitivity to immunotherapy. This study intended to explore the relationship between ARID1A expression and SIR, and to further elucidate the prognostic value of ARID1A expression in gastric cancer (GC). The mRNA and protein expression of ARID1A were detected in 272 formalin-fixed paraffin-embedded (FFPE) tumor tissues. The data of nine systemic inflammation markers were collected 1 week before gastrectomy. Univariate and multivariate COX analysis were used to screen out independent predictors of GC. Negative expression of ARID1A protein was related to GC with deficient mismatch repair (dMMR) (p = 0.033), positive programmed cell death-ligand 1 (PD-L1) (p = 0.005) and lower albumin level (p = 0.0064). Low expression of ARID1A mRNA was common in GC with abnormal E-cadherin (p = 0.020) and a higher platelet/lymphocyte ratio (PLR) (p = 0.0391). Multivariate COX analysis showed that the expression of ARID1A protein (p = 0.023), age (p = 0.004), T stage (p = 0.009) and N stage (p = 0.009) were independent predictors of GC. The nomogram established by independent predictors can accurately evaluate the survival risk of patients with GC. The loss of ARID1A protein expression was associated with the dMMR subtype and high expression of PD-L1 in GC. Negative ARID1A protein and low expression of mRNA were associated with aberrant systemic inflammatory markers. The expression of ARID1A protein had important prognostic significance in GC.
Highlights
Gastric cancer (GC) is the sixth most common type of malignancy and the fourthleading cause of global cancer-related death(Sung et al 2021)
The loss of ARID1A protein expression was associated with microsatellite instability-high (MSI-H) subtype and high expression of programmed cell deathligand 1 (PD-L1) in gastric cancer (GC)
Negative ARID1A protein and low expression of mRNA were associated with aberrant systemic inflammatory markers
Summary
Gastric cancer (GC) is the sixth most common type of malignancy and the fourthleading cause of global cancer-related death(Sung et al 2021). CHECKMATE-649 has revealed that nivolumab combined with chemotherapy have more superior OS than chemotherapy alone in advanced GC and EGJ cancer(13.8 months vs 11.6 months) especially when PD-L1 CPS≥5 (14.4 months vs 11.1 months), nivolumab plus chemotherapy were approved by the FDA as a new standard first-line treatment for advanced GC and EGJ cancer in 2021(Janjigian et al 2021) These remarkable results illustrated the value of PD-L1 expression level in guiding the use of ICIs. Another research showed that patients with microsatellite instability-high (MSI-H) or Epstein-Barr virus (EBV)positive metastatic GCs had a significantly higher overall response rate (ORR) to pembrolizumab (85.7% and 100%, respectively)(S. In a recent phase Ib/II clinical trial (NCT02915432), high tumor mutational burden (TMB-H) was significantly associated with better OS compared low tumor mutational burden (TMB-L) group in advanced GC receiving immunotherapy (14.6 months vs 4.0 months)(Wang et al 2019) These studies provided reliable basis for identifying biomarkers of ICB therapy. This study intended to explore the relationship between ARID1A expression and SIR, and to further elucidate the prognostic value of ARID1A expression in gastric cancer (GC)
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