Cutaneous melanoma (CM) is a life-threatening form of skin cancer.,Prognostic biomarkers can reliably stratify patients at initial melanoma diagnosis according to risk, and may inform clinical decisions.,Here, we performed a retrospective, cohort-based study analyzing genome-wide DNA methylation of 461 patients with CM from the TCGA database.,Cox regression analyses were conducted to establish a four-DNA methylation signature that was significantly associated with the overall survival (OS) of patients with CM, and that was validated in an independent cohort.,Corresponding Kaplan-Meier analysis displayed a distinct separation in OS.,The ROC analysis confirmed that the predictive signature performed well.,Notably, this signature exhibited much higher predictive accuracy in comparison with known biomarkers.,This signature was significantly correlated with immune checkpoint blockade (ICB) immunotherapy-related signatures, and may have potential as a guide for measures of responsiveness to ICB immunotherapy.
Melanoma is currently divided on a genetic level according to mutational status.,However, this classification does not optimally predict prognosis.,In prior studies, we have defined gene expression phenotypes (high-immune, pigmentation, proliferative and normal-like), which are predictive of survival outcome as well as informative of biology.,Herein, we employed a population-based metastatic melanoma cohort and external cohorts to determine the prognostic and predictive significance of the gene expression phenotypes.,We performed expression profiling on 214 cutaneous melanoma tumors and found an increased risk of developing distant metastases in the pigmentation (HR, 1.9; 95% CI, 1.05-3.28; P=0.03) and proliferative (HR, 2.8; 95% CI, 1.43-5.57; P=0.003) groups as compared to the high-immune response group.,Further genetic characterization of melanomas using targeted deep-sequencing revealed similar mutational patterns across these phenotypes.,We also used publicly available expression profiling data from melanoma patients treated with targeted or vaccine therapy in order to determine if our signatures predicted therapeutic response.,In patients receiving targeted therapy, melanomas resistant to targeted therapy were enriched in the MITF-low proliferative subtype as compared to pre-treatment biopsies (P=0.02).,In summary, the melanoma gene expression phenotypes are highly predictive of survival outcome and can further help to discriminate patients responding to targeted therapy.