Aberrant DNA Methylation Predicts Melanoma-Specific Survival in Patients with Acral Melanoma.

Dinesh Pradhan,Varshini Vasudevaraja,Priyadharsini Nagarajan,Phyu P Aung,Ravesanker Ezhilarasan,Victor G Prieto,Lihong Long,Adi Diab,Erik P Sulman,Denái Milton,Doina Ivan,Yingwen Ding,George Jour,Carlos Antonio Torres-Cabala,Jonathan L Curry,Wen-Jen Hwu,Michael T Tetzlaff

doi:10.3390/cancers11122031

Dinesh Pradhan, Varshini Vasudevaraja + Show 15 more

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https://doi.org/10.3390/cancers11122031

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Abstract

Acral melanoma (AM) is a rare, aggressive type of cutaneous melanoma (CM) with a distinct genetic profile. We aimed to identify a methylome signature distinguishing primary acral lentiginous melanoma (PALM) from primary non-lentiginous AM (NALM), metastatic ALM (MALM), primary non-acral CM (PCM), and acral nevus (AN). A total of 22 PALM, nine NALM, 10 MALM, nine PCM, and three AN were subjected to genome-wide methylation analysis using the Illumina Infinium Methylation EPIC array interrogating 866,562 CpG sites. A prominent finding was that the methylation profiles of PALM and NALM were distinct. Four of the genes most differentially methylated between PALM and NALM or MALM were HHEX, DIPK2A, NELFB, 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 survival (DSS) than patients with PALM. Aberrant methylation was significantly associated with aggressive clinicopathologic parameters and worse DSS. 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 and may be leveraged for the development of targeted therapies.

Highlights

Primary cutaneous melanomas (CMs) arising from the glabrous skin of the palms, soles, or nail apparatus are considered acral melanomas (AMs)
When we compared primary acral lentiginous melanoma (PALM) and metastatic acral lentiginous melanoma (ALM) (MALM), we found that the four promoter-associated probes above-mentioned were among the most differentially methylated
In agreement with previous studies on CM, we identified significant associations between aberrant methylation and aggressive clinicopathologic parameters in AM including the presence of lymph node metastasis, ulceration, increased mitoses, and higher Breslow thickness [21,22,23,24,25,26]

Summary

Introduction

Primary cutaneous melanomas (CMs) arising from the glabrous skin of the palms, soles, or nail apparatus are considered acral melanomas (AMs). Most AMs exhibit a lentiginous proliferation within the epidermis and are referred to as acral lentiginous melanoma (ALM), a rare subtype characterized by increased risk of metastasis and melanoma-specific death [1,2,3]. ALM is the most common melanoma subtype in African American, Hispanic, and Asian individuals, accounting for 29% to 72% of CM cases in these populations [7,8,9]. Whereas melanoma on sun-exposed sites harbors a large number of ultraviolet light–induced mutations commonly affecting genes regulating the MAPK pathway, it has been reported that AM is driven by a combination of amplifications of TERT, CCND1, CDK4, MITF, PAK1, GAB2, YAP1, and MDM2 and mutations in BRAF, NRAS, KIT, and PDGFRA [10,11,12,13]

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