Abstract LB386: Aberrant DNA polymerase beta expression is associated with dysregulated tumor immune microenvironment and its prognostic value in gastric cancer

Abstract Background: Gastric cancer (GC) is a leading cause of cancer-related deaths globally. Emerging evidence implicates aberrant DNA polymerase beta (POLB) expression in genomic instability and tumorigenesis. Previously, we demonstrated that the human gastric cancer-associated variant of POLB (Leu22Pro or L22P) lacks dRP lyase function in vitro and induces replication associated genomic instability and cellular transformation. In addition , in vivo mouse model experiment has shown that L22P mutation of POLB , leads to inefficient BER and exacerbate genomic instability and carcinogenesis . Methods: We conducted an in-silico analysis of GC datasets from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) to assess POLB expression levels and their association with the tumor immune microenvironment (TIME). Survival analyses were performed using Kaplan-Meier estimates, and the TIMER algorithm was employed to evaluate immune cell infiltration. In parallel, we utilized a dRP lyase-deficient POLB variant (Leu22Pro, L22P) in vivo model to investigate the impact of dRP lyase deficient POLB on genomic stability and inflammatory signaling. Also, Mitotic dysfunction and cytosolic DNA-mediated inflammatory responses were assessed, with and without poly(ADP-ribose) polymerase 1 (PARP1) inhibition. Results: Our analysis revealed that POLB is overexpressed in approximately 32% of GC cases, significantly correlating with the intestinal subtype of GC. POLB overexpression was associated with reduced expression of innate immune signaling genes and lower infiltration of immune cells, indicating a suppressed immune microenvironment. Conversely, tumors with high POLB expression exhibited increased mutation frequency and microsatellite instability (MSI). Notably, patients with POLB-overexpressing tumors and high immune score demonstrated improved overall survival. ROC analysis suggested that POLB overexpression holds potential as a prognostic marker for GC. In in vivo model, the L22P POLB variant increased mitotic dysfunction-associated genomic instability, leading to a cytosolic DNA-mediated inflammatory response. PARP1 inhibition exacerbated chromosomal instability and enhanced the inflammatory response in these cells. Conclusions: Aberrant POLB expression in GC is associated with a dysregulated TIME and may serve as a prognostic indicator. Defective POLB function contributes to genomic instability and activates cytosolic DNA-mediated inflammatory signaling. These findings suggest that deregulated POLB in tumor likely provide a potential opportunity to patient stratification for better immune-based therapies in GC. Citation Format: Aashirwad Shahi, Shengyuan Zhao, Dawit Kidane. Aberrant DNA polymerase beta expression is associated with dysregulated tumor immune microenvironment and its prognostic value in gastric cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB386.