ABSTRACT: Epigenetic signatures of alm and assoication with outcome. Background: Acral melanoma (AM) is a rare, aggressive type of cutaneous melanoma (CM) with a distinct genetic profile for which comprehensive genome-wide methylation analysis (GWMA) is lacking. We aimed to identify a methylome signature distinguishing primary acral lentiginous melanoma (PALM) from primary non-lentiginous AM involving the acral sites (NALM), metastatic ALM (MALM), primary non-acral CM (PCM), and acral nevus (AN). Methods: A total of 22 PALM, 9 NALM, 10 MALM, 9 PCM, and 3 AN cases were subjected to GWMA using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites, and their methylomes were compared. Results: A prominent finding was that the methylation profiles of PALM and NALM were distinct, although both are considered canonical AMs. Four of the genes most differentially methylated between PALM and NALM or PALM and MALM were HHEX, DIPK2A (formerly C3orf58), NELFB (formerly COBRA1), and TEF. However, when primary AMs (PALM+NALM) were compared with MALM, IFITM1 and SIK3 were the most differentially methylated, highlighting their pivotal role in the metastatic potential of AMs. Patients with NALM had significantly worse disease-specific (DSS) and overall survival than patients with PALM. Aberrant methylation was significantly associated with aggressive clinicopathologic parameters, including greater Breslow thickness, ulceration, increased mitotic rate, and lymph node metastasis, and with worse DSS. Conclusion: Our study emphasizes the importance of distinguishing the two epigenetically distinct subtypes of AM. We also identified novel epigenetic prognostic biomarkers that may serve to risk-stratify patients with AM. These epigenetic alterations may be leveraged for development of targeted therapies.
