DNA Methylation Markers Of Early Stage Invasion Strategies In Primary Malignant Melanoma

Szilvia ECSEDI, Internatinal Agency for Research on Cancer, France
KOROKNAI V. 2,4 , SZASZ I. 2,4 , CUENIN C. 1 , FERNANDEZ-JIMENEZ N. 1 , LE CALVEZ-KELM F. 3 , DURAND G. 3 , BALAZS M. 2,4 , HERCEG Z. 1 , HERNANDEZ-VARGAS H. 1

1 Internatinal Agency for Research on Cancer, Mechanisms of Carcinogenesis, Epigenetics Group, Lyon, France
2 Hungarian Academy of Sciences Public Health Research Group, University of Debrecen, Debrecen, Hungary
3 International Agency for Research on Cancer, Section of Genetics, Genetic Cancer Susceptibility Group, Lyon, France
4 Faculty of Public Health, Department of Preventive Medicine, University of Debrecen, Debrecen, Hungary

Purpose: the high mortality rate of melanomas is primarily due to the aggressive metastatic capacity of the tumours. Studies performed so far have accordingly aimed at examining the metastatic disease, while melanomagenesis remains unclear. Because epigenetics provides a valuable tool for biomarkers that can serve as targets for early detection, we attempted to characterize the DNA methylation markers of primary melanomas, which associated with local invasion.
Methods: studying the invasive potential of multiple cell lines derived from primary melanomas was followed by subcultures of invasive clones. Epigenome-wide paired analyses were done in invasive and non-invasive clones by Illumina Methylation arrays; to gain a functional view of the epigenetic changes, we studied gene expression patterns by Affymetrix arrays.
Results: we described a methylation pattern associated with invasion, which involved promoter hypermethylation and decreased expression of genes playing a role in proliferation. Several methylation changes were visible for genes responsible for the mesenchymal transition strategies. Gene body methylation changes affecting TEAD1 master transcription factors and genes of amoeboid transition pathways were also detected. Experimental validation of both the methylation and gene expression results are in progress as well as in silico validation, using the publicly available data. As a next step, we will apply melanoma tissues – from nevi through in situ and to vertical growth phase tumours – in order to infer at which point the invasiveness related methylation changes occur.
Conclusions: our study can contribute to a conceptual change of shifting the focus from therapeutic interventions of the metastatic tumours towards promoting early detection as well as more accurate prognostication of melanomas.
Funding source: the research was supported by the European Union and the State of Hungary, co-financed by the European Social Fund in the framework of the TÁMOP-4.2.4.A/2-11/1-2012-0001 ‘National Excellence Program’; by IARC Postdoctoral Fellowship and Marie Curie Actions-People-COFUND.