CNDP1 Overexpression by Promoter Hypomethylation Predicts Poor Prognosis and Immunotherapy Response in Mucosal Melanoma

Abstract

Mucosal melanoma (MM) is an uncommon and aggressive malignant tumor, characterized by a scarcity of effective treatment options and novel biomarkers. To develop novel biomarkers, a total of 89 MM tumor samples (including 50 cases in the discovery cohort and 39 cases in the validation cohort) were collected from three medical centers. Targeted bisulfite sequencing and RNA sequencing were conducted in the discovery cohort, and Cox regression analysis was employed to evaluate DNA methylation (methyDNA) and RNA expression data. Our results revealed that, compared to control samples, MM tumor samples exhibited a hypomethylated status of the Carnosine dipeptidase 1 (CNDP1) promoter (p < 0.001), which significantly up-regulated its gene expression (R = −0.815, p < 0.001) and indicated a worse prognosis (p = 0.002, hazard ratio (HR) (95% confidence interval, CI) = 0.01 (6.78E-04 ~ 0.20)). Using immunohistochemical staining, we found that CNDP1 protein was expressed in 81.8% of MM cases (36/44, including 1+/2+/3+), and high expression (2+/3+) was associated with significantly decreased overall survival (p = 0.0120, HR (95% CI) = 2.693 (1.223–5.931)). This pattern is consistent across both discovery and validation cohorts. Moreover, among the 21 patients who received immunotherapy, those with hypomethylated CNDP1 were associated with a ‘cold’ tumor immune microenvironment and suboptimal therapeutic outcomes (Objective Response Rate: 38% vs. 60%; Disease Control Rate: 75% vs. 100%). In conclusion, the overexpression of CNDP1, driven by promoter hypomethylation, may serve as a potential predictor of poor prognosis and diminished response to immunotherapy in MM.