The observed variability in HLA-G expression in each TCGA cohort and human cancer cell line (i.e., melanoma: M8/HLA-G−, 1074mel/HLA-G−, and FON/HLA-G+) examined could be related to the nucleotide genomic variations in cancer cell lines and patients with cancer, nucleotide variations in specific HREs for HIF-1 (during hypoxia conditions), and CpG methylation status in HLA-G 5′UTR. This evidence concerns the gene HLA-G and melanoma.