Mucosal
melanoma exhibits limited responsiveness to anti-PD-1
therapy. However, a subgroup of mucosal
melanomas, particularly those situated at specific anatomical sites like primary
malignant melanoma of the esophagus (
PMME), display remarkable sensitivity to anti-PD-1 treatment. The underlying mechanisms driving this superior response and the DNA methylation patterns in mucosal
melanoma have not been thoroughly investigated. We collected
tumor samples from 50 mucosal
melanoma patients, including 31
PMME and 19 non-esophageal mucosal
melanoma (NEMM). Targeted
bisulfite sequencing was conducted to characterize the DNA methylation landscape of mucosal
melanoma and explore the epigenetic profiling differences between
PMME and NEMM. Bulk
RNA sequencing and multiplex immunofluorescence staining were performed to confirm the impact of methylation on gene expression and immune microenvironment. Our analysis revealed distinct epigenetic signatures that distinguish mucosal
melanomas of different origins. Notably,
PMME exhibited distinct epigenetic profiling characterized by a global hypermethylation alteration compared to NEMM. The prognostic model based on the methylation scores of a 7-DMR panel could effectively predict the overall survival of
PMME patients and potentially serve as a prognostic factor.
PMME displayed a substantial enrichment of immune-activating cells in contrast to NEMM. Furthermore, we observed hypermethylation of the TERT promoter in
PMME, which correlated with heightened CD8+ T cell infiltration, and patients with hypermethylated TERT were likely to have improved responses to
immunotherapy. Our results indicated that
PMME shows a distinct methylation landscape compared with NEMM, and the epigenetic status of TERT might be used to estimate prognosis and direct anti-PD-1 treatment for mucosal
melanoma.