WDR49 mutation as a novel predictive biomarker in patients with non–small cell lung cancer with immune checkpoint inhibitors.

Abstract

2615 Background: Application of Immune Checkpoint Inhibitors (ICIs) has become the first-line therapy for advanced or metastatic non-small cell lung cancer (NSCLC). WDR49 gene belongs to the WDR (WD40-repeat) protein family which participates in a wide range of biological processes, including DNA damage repair and immune regulation, etc. However, the correlation between WDR49 mutation and immune efficacy is unclear. Methods: A total of three independent cohorts of NSCLC patients treated with immunotherapy were analyzed in this study: the Miao cohort (n = 56), the Rizvi cohort (n = 34), the Hellmann cohort (n = 75). Survival was estimated by Kaplan-Meier curves, with the p value determined by a log-rank test. HR was determined through the univariable and multivariable Cox regression. The CIBERSORT analysis relied on RNA-seq data in The Cancer Genome Atlas (TCGA) database. Two-sided P value < 0.05 was considered statistically significant. All the statistical analyses were conducted with R version 4.0.3. Results: In this merged cohort, the frequency of WDR49 mutation ( WDR49-mut) was 10.30% (17 in 165), and most patients with WDR49 mutation were lung adenocarcinoma (LUAD) (11.85%, 16 in 135). Meanwhile, the frequency of WDR49-mut in TCGA database was 7.05 % and 3.84% in LUAD and lung squamous cell carcinoma (LUSC), respectively. The Kaplan-Meier curves survival analysis indicated that WDR49-mut was associated with longer progression free survival (PFS) (median PFS 23 months vs 5.2 months, hazard ratio [HR] = 0.17 [95% CI, 0.06–0.47], P < 0.001) and higher objective response rate (ORR) (76% vs 27%, P < 0.001). Furtherly, WDR49-mut was significantly related to higher tumor mutational burden (TMB) (median TMB 495 vs 149, P < 0.001), but it had nothing to do with the expression of PD-L1 (Proportion of PD-L1 positive 72.7% vs 68.5%, P = 1). The CIBERSORT analysis revealed that CD8+ T cell infiltration was significantly higher in WDR49-mut group than WDR49 wildtype group (p < 0.05). Conclusions: Better treatment response and survival benefit in the mutant group suggest that the WDR49 mutation may serve as a novel predictive biomarker in NSCLC patients with ICIs. The significantly higher TMB and CD8+ T cell infiltration in WDR49-mut group may be the potential mechanism.