LINE-1 hypermethylation in peripheral blood of cutaneous melanoma patients is associated with metastasis

Abstract

Aberrant DNA methylation pattern is a well-known epigenetic marker of cancer cells. Recently, aberrant methylation was also reported in the peripheral blood of cancer patients and it could potentially serve as a biomarker for cancer risk. We investigated the methylation pattern of LINE-1 and other repetitive DNA elements in peripheral blood of cutaneous melanoma patients in order to search for an association with clinical characteristics. The patient cohort was composed by 69 unrelated melanoma patients, 28 of whom were hereditary cases (with or without CDKN2A mutations) and 41 were isolated (sporadic) melanoma cases. Methylation of LINE-1 was evaluated by pyrosequencing, whereas additional repetitive DNA sequences were assessed using Illumina 450K methylation microarray. Melanoma patients exhibited a higher, albeit heterogeneous, LINE-1 methylation level compared with controls. Hereditary melanoma patients carrying CDKN2A mutations showed a hypermethylated pattern of both LINE-1 and repetitive DNA elements compared with other patients. In particular, the methylation level at one specific CpG of LINE-1 was found to be correlated with the occurrence of metastasis. Our data suggest that LINE-1 hypermethylation in peripheral blood of melanoma patients is a potential epigenetic biomarker for metastasis occurrence.

LINE-1 hypermethylation in white blood cell DNA is associated with high-grade cervical intraepithelial neoplasia

“…Several studies have shown reduced LINE-1 methylation levels in cancer tissues and WBCs, especially in patients with head and neck, bladder and gastric cancer [ 27 – 32 ]. In contrast, other studies on bladder, renal, colorectal, ovarian, pancreatic cancers and cutaneous melanoma have reported higher LINE-1 methylation levels in WBCs of cancer patients [ 20 – 26 ]. A plausible explanation for this relationship is that LINE-1 sequences with double strand DNA breaks had higher methylation levels around the area of the break, compared to DNA without double strand breaks [ 51 ].…”

“…Secondly, previous studies have reported that differences in blood cell composition could lead to variation in methylation levels [ 70 ]. In our study, DNA was extracted from whole blood and differences in the proportion of blood cell subtypes could represent a limitation of this study, reinforcing the importance of accounting for cellular heterogeneity in clinical practice and research [ 26 ].…”

Global methylation of blood leukocyte DNA and risk of melanoma

“…Selected elements might show an opposite trend, or have detectable methylation changes in blood only after the initiation of melanoma. Intriguingly, LINE-1 hypermethylation in peripheral blood is a potential indicator for the occurrence of metastasis 29 . In fact, measurement of 5-mC level has been used widely as an alternate marker for global DNA methylation in the entire genome 5, 11 .…”

DNA Methylation Levels of Melanoma Risk Genes Are Associated with Clinical Characteristics of Melanoma Patients

“…Aberrant DNA methylation is usually an early and stable event in tumorigenesis and could be used for detecting and monitoring diseases [ 32 ]. Previous studies in melanoma and surrogate samples have revealed epigenetic markers based on methylation patterns of LINE-1 [ 33 , 34 ] , RASSF1A [ 35 ], TSLC1 [ 36 ],and MGMT [ 37 ]. In this study, we have investigated the methylation levels of twelve melanoma genes to evaluate their potential role as predisposition factors and/or biomarkers.…”