To investigate the role of the CpG Island Methylator Phenotype (CIMP) in cutaneous melanoma.
Approach:
Data Analysis: Analyzed DNA methylation and transcriptomic data from The Cancer Genome Atlas (TCGA) and validated findings in an external cohort (GSE120878).
Unsupervised Clustering: Identified CIMP subtypes through unsupervised clustering methods.
Integrative Analysis: Conducted integrative analyses including promoter-focused methylation–expression coupling, immune deconvolution, genomic profiling, and drug sensitivity prediction.
Clinical Assessment: Assessed clinical relevance in an independent cohort of patients treated with immune checkpoint blockade.
Functional Assays: Evaluated the role of NRAS in melanoma cell lines through functional assays.
Key Findings:
Two epigenetic subtypes were defined: CIMP+ (24.9%) and CIMP− (75.1%).
CIMP+ tumors were linked to older age and male sex.
CIMP+ tumors exhibited an immune-depleted profile with reduced immune checkpoint gene expression.
CIMP+ tumors were enriched for NRAS and ARID2 mutations and showed increased genomic instability.
In an ICB-treated cohort, CIMP+ status was significantly enriched in non-responders.
Interpretation:
CIMP defines a melanoma subtype associated with poor prognosis and reduced benefit from immunotherapy, highlighting its role in therapeutic resistance.
Limitations:
The study primarily focused on late-stage melanoma, limiting insights into early-stage disease.
The complexity of tumor microenvironment interactions may not be fully captured, potentially affecting the findings.
Conclusion:
CIMP is a clinically relevant melanoma subtype characterized by epigenetic remodeling and an immune-poor microenvironment, suggesting multifactorial therapeutic resistance.
