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

Abstract

In melanoma development, oncogenic process is mediated by genetic and epigenetic mutations, and few studies have so far explored the role of DNA methylation either as predisposition factor or biomarker. We tested patient samples for germline CDKN2A methylation status and found no evidence of inactivation by promoter hypermethylation. We have also investigated the association of clinical characteristics of samples with the DNA methylation pattern of twelve genes relevant for melanomagenesis. Five genes (BAP1, MGMT, MITF, PALB2, and POT1) presented statistical association between blood DNA methylation levels and either CDKN2A-mutation status, number of lesions, or Breslow thickness. In tumors, five genes (KIT, MGMT, MITF, TERT, and TNF) exhibited methylation levels significantly different between tumor groups including acral compared to nonacral melanomas and matched primary lesions and metastases. Our data pinpoint that the methylation level of eight melanoma-associated genes could potentially represent markers for this disease both in peripheral blood and in tumor samples.

Aberrant DNA methylation is associated with aggressive clinicopathological features and poor survival in cutaneous melanoma

“…In this regard, ageing has been described as a major contributing factor to hypermethylation in cancer . Consistent with previous reports, we found DNA methylation differences between acral and nonacral melanomas . Acral melanoma is an uncommon subtype with no association with sun exposure, which occurs frequently in older patients.…”

Line-1 Hypomethylation and Mutational Status in Cutaneous Melanomas

“…Taken together, these recent reports demonstrate that the pattern of LINE-1 methylation in blood is quite variable, in a clear contrast to tumor samples, which in general exhibit a genome-wide hypomethylation. We have previously reported an apparent contrast between the LINE-1 methylation pattern detected in the blood of patients with melanoma (hypermethylation) and in primary melanomas (hypomethylation) 34. The biological explanation for this discrepancy, and even for methylation differences detected in blood, remains elusive.…”

Applications of Systems Biology to Identify Mechanisms of Adaptive Response to Targeted Single and Combinatorial Drug Treatment in Cancer

“…As previously discussed, changes in DNA methylation often serve to silence tumor suppressors and have been observed in multiple cancers, including melanoma (de Araújo et al, 2015). To ascertain the effects of treatment on DNA methylation status, we profiled the basal methylome of our cell lines, and DM331 was subjected to the same panel of treatments as performed for gene expression.…”

“…This indicates that MAPK pathway inhibition or RTK inhibition are insufficient to induce changes in DNA methylation at 8 hours. As with our other analyses of functional genomics data, we were curious to know whether DNA methylation status serves as a marker of sensitivity or synergy in our panel, as other studies had shown that DNA methylation is an effective profiling tool for patient outcome (de Araújo et al, 2015;Conway et al, 2011;Thomas et al, 2014). …”

“…DNA methylation is an epigenetic mechanism thought to stabilize the silencing of genes (Thomas et al, 2014) and has been observed to have functional significance in colorectal, gastric, and breast cancers (de Araújo et al, 2015;Gazzoli et al, 2002;Pinheiro et al, 2010;Venkatachalam et al, 2010;Wong et al, 2011). Limited work has been done in melanoma with regards to DNA methylation state, but preliminary studies suggest that it plays a significant role in mechanisms of resistance (de Araújo et al, 2015). It is uncertain as to whether the adaptive response to vemurafenib treatment utilizes changes in DNA methylation, but it has been observed that DNA methylation profiles are associated with clinical outcomes (Thomas et al, 2014).…”