Ecsedi Szilvia, Hernandez-Vargas Hector, Lima Sheila C, Vizkeleti Laura, Toth Reka, Lazar Viktoria, Koroknai Viktoria, Kiss Timea, Emri Gabriella, Herceg Zdenko, Adany Roza, Balazs Margit
Department of Preventive Medicine, Faculty of Public Health, University of Debrecen, Debrecen, Hungary; MTA-DE- Public Health Research Group, University of Debrecen, Debrecen, Hungary.
International Agency for Research on Cancer, Section of Mechanisms of Carcinogenesis, Epigenetics Group, Lyon, France.
PLoS One. 2014 May 15;9(5):e96612. doi: 10.1371/journal.pone.0096612. eCollection 2014.
In melanoma, the presence of promoter related hypermethylation has previously been reported, however, no methylation-based distinction has been drawn among the diverse melanoma subtypes. Here, we investigated DNA methylation changes associated with melanoma progression and links between methylation patterns and other types of somatic alterations, including the most frequent mutations and DNA copy number changes. Our results revealed that the methylome, presenting in early stage samples and associated with the BRAF(V600E) mutation, gradually decreased in the medium and late stages of the disease. An inverse relationship among the other predefined groups and promoter methylation was also revealed except for histologic subtype, whereas the more aggressive, nodular subtype melanomas exhibited hypermethylation as well. The Breslow thickness, which is a continuous variable, allowed for the most precise insight into how promoter methylation decreases from stage to stage. Integrating our methylation results with a high-throughput copy number alteration dataset, local correlations were detected in the MYB and EYA4 genes. With regard to the effects of DNA hypermethylation on melanoma patients' survival, correcting for clinical cofounders, only the KIT gene was associated with a lower overall survival rate. In this study, we demonstrate the strong influence of promoter localized DNA methylation changes on melanoma initiation and show how hypermethylation decreases in melanomas associated with less favourable clinical outcomes. Furthermore, we establish the methylation pattern as part of an integrated apparatus of somatic DNA alterations.
在黑色素瘤中，此前已有关于启动子相关高甲基化存在的报道，然而，尚未在不同的黑色素瘤亚型之间基于甲基化进行区分。在此，我们研究了与黑色素瘤进展相关的DNA甲基化变化以及甲基化模式与其他类型体细胞改变之间的联系，包括最常见的突变和DNA拷贝数变化。我们的结果显示，存在于早期样本中且与BRAF（V600E）突变相关的甲基化组在疾病的中晚期逐渐减少。除了组织学亚型外，在其他预定义组与启动子甲基化之间也发现了相反的关系，而侵袭性更强的结节型亚型黑色素瘤也表现出高甲基化。作为连续变量的数据， Breslow厚度能够最精确地洞察启动子甲基化如何随阶段降低。将我们的甲基化结果与高通量拷贝数改变数据集相结合，在MYB和EYA4基因中检测到了局部相关性。关于DNA高甲基化对黑色素瘤患者生存的影响，在校正临床混杂因素后，只有KIT基因与较低的总生存率相关。在本研究中，我们证明了启动子局部DNA甲基化变化对黑色素瘤起始的强烈影响，并展示了在临床预后较差的黑色素瘤中高甲基化是如何降低的。此外，我们将甲基化模式确立为体细胞DNA改变综合机制的一部分。
