A, Schematic depicting the workflow utilized to analyze transcriptomes of APOE2 and APOE4 carrier melanomas in the TCGA-SKCM cohort (WES, whole exome sequencing). Created with BioRender.com. B, Top ten pathways upregulated in primary tumors of APOE2 carrier patients (n=14) relative to APOE4 carrier patients (n=19) as determined by GSEA and ranked by adjusted p-value (NES, normalized enrichment score; padj, adjusted p-value). C, Top ten pathways upregulated in metastases of APOE2 carrier patients (n=30) relative to APOE4 carrier patients (n=85) as determined by GSEA and ranked by adjusted p-value. D, Model depicting our current understanding of the role of common APOE genetic variants in melanoma progression. The model depicts APOE4 acting as a suppressor of melanoma progression by enhancing anti-tumor immunity as well as repressing angiogenesis and invasion. In contrast, APOE2 is shown as a driver of melanoma progression through its stimulation of protein synthesis via the LRP1 receptor. Created with BioRender.com.