TY - JOUR
T1 - Aberrant DNA methylation predicts melanoma-specific survival in patients with acral melanoma
AU - Pradhan, Dinesh
AU - Jour, George
AU - Milton, Denái
AU - Vasudevaraja, Varshini
AU - Tetzlaff, Michael T.
AU - Nagarajan, Priyadharsini
AU - Curry, Jonathan L.
AU - Ivan, Doina
AU - Long, Lihong
AU - Ding, Yingwen
AU - Ezhilarasan, Ravesanker
AU - Sulman, Erik P.
AU - Diab, Adi
AU - Hwu, Wen Jen
AU - Prieto, Victor G.
AU - Torres-Cabala, Carlos Antonio
AU - Aung, Phyu P.
N1 - Publisher Copyright:
© 2019 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2019/12
Y1 - 2019/12
N2 - 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.
AB - 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.
KW - Acral lentiginous melanoma
KW - Cutaneous melanoma
KW - Epigenetics
KW - Methylation
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U2 - 10.3390/cancers11122031
DO - 10.3390/cancers11122031
M3 - Article
C2 - 31888295
AN - SCOPUS:85077266465
SN - 2072-6694
VL - 11
JO - Cancers
JF - Cancers
IS - 12
M1 - 2031
ER -