In conclusion, we have identified four novel epigenetic prognostic biomarkers in AM: HHEX, NELFB, IFITM1, and SIK3. Hypermethylation in the promoter region of these genes is significantly associated with aggressive clinicopathologic parameters including greater Breslow thickness, ulceration, increased mitotic rate, and lymph node metastasis and worse DSS in AM. This evidence concerns the gene HHEX and metastatic malignant neoplasm in the lymph nodes.