The Polymerase Epsilon Gene Expression and Mutation Predictive Significance in Patients Receiving Immune Checkpoint Inhibitors (icis) for Non-small Cell Lung Cancer (NSCLS)
Recommended Citation
Alshurafa A, Alhushki S, Alfaqheri D, Abushukair H, Alzghoul BN, Abu Rous F. The Polymerase Epsilon Gene Expression and Mutation Predictive Significance in Patients Receiving Immune Checkpoint Inhibitors (icis) for Non-small Cell Lung Cancer (NSCLS). Am J Respir Crit Care Med 2024; 209.
Document Type
Conference Proceeding
Publication Date
5-20-2024
Publication Title
Am J Respir Crit Care Med
Abstract
Rationale The DNA polymerase epsilon enzyme encoded by the POLE (polymerase epsilon) gene has drawn much interest as a potential biomarker for immunotherapy response. In this study, we used multi-omics analysis to assess the predictive and prognostic utility of POLE mutation in (NSCLC) patients treated with (ICIs). Methods Our study utilized The Cancer Genomic Atlas (TCGA) pan-cancer lung adenocarcinoma (LUAD, n=566), squamous cell carcinoma (LUSC, n=487), and (MSK) Immunotherapy NSCLC (n=350) in our analysis. Clinical and genomic data were obtained through cBioportal. Using bulk tissue RNAseq, immune cell infiltration was assessed using the web-based TIMER2.0 tool. To further understand the synergy between POLE gene expression and immune cell infiltration, we conducted a subgroup analysis by different levels of POLE gene expression and different levels of immune cell infiltration using Cox proportional hazard model with correction for age, stage, gender, and race. Results POLE mutation frequencies in the combined LUAD and LUSC group were 5.1% and 5.4%, respectively. In the LUAD cohort, POLE mutations were significantly associated with poor overall survival outcomes (median: 30.54 vs. 49.84 months; Log-rank p=0.0269) as compared to POLE wild-type. Notably, POLE mutations were associated with better overall survival than POLE wild-type in patients receiving ICI for NSCLC (median: NA vs. 11.00; p=0.0365). Furthermore, in the NSCLC cohort, the tumor mutation burden was significantly higher in the POLE mutant group as compared to the wild-type (median: 19.89 vs 6.85; p<0.001). In addition, POLE mutations in LUAD were significantly (p<0.05) associated with increased infiltration of CD8+ T-cells and lower levels of macrophage M2 and cancer-associated fibroblasts infiltration. After adjusting for age, stage gender, and race, patients with high POLE gene expression experienced significant better overall survival benefit with high CD8+ T-cell infiltration compared to those with low CD8+ T-cell infiltration. Furthermore, in patients with high CD8+ T-cell infiltration, there was a trend for enhanced overall survival benefit in patients with high POLE gene expression compared to those with low gene expression. Conclusion Our analysis revealed a positive predictive value of POLE mutations in NSCLC patients receiving Immune checkpoint Inhibitors, and a negative prognostic effect in LUAD non-ICI-treated patients. Furthermore, our exploratory work highlights a potential synergistic effect between POLE expression and CD8+ Tcell infiltration. Further investigations are required to offer mechanistic insights into the impact of POLE mutations and expression.
Volume
209
