Dissecting DNA methylation changes arising during transition of melanocytes to various melanocytic lesions of the skin and uvea.

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Melanoma is considered to arise from melanocytic progenitor cells as a result of (mostly) somatic mutations. Remarkably, melanomas arising in different tissues (e.g. skin or eye) are not only clinically different but also characterized by different mutation patterns, thus representing different tumor entities. We assume that the melanocytic precursors in the skin and the choroid are already different cell types and thus differ by characteristic DNA methylation patterns. Nevi can arise from melanocytes by clonal expansion and often already carry some of the oncogenic mutations (GNAQ/11 or BRAF) characteristic of the particular melanoma type. They are therefore considered benign intermediate stages in the carcinogenesis of uveal (UM) and cutaneous melanoma (CM). The nature and extent of the difference between melanocytes and nevi of the skin and eye are not well understood. Here we aim to perform a genome-wide DNA methylation analysis of autosomal CpGs in melanocytes, nevi, primary melanomas, and metastases of both cutaneous and uveal melanocytic lineages. Methylation analysis is performed at the level of individual CpGs using EM-Sequencing. Using established algorithms, we will identify regions that exhibit dynamic tissue- or stage-dependent methylation differences. By comparing the methylation patterns of cutaneous and uveal melanocytes, we aim to determine whether and in what aspects melanocytes differ in skin and choroid. Since large parts of the methylation pattern of the cell of origin are retained in tumors, it can be assumed that the identified differences are also present in primary tumors and thus contribute to the difference between the two tumor entities. In addition, we aim to determine epigenetic markers (differentially methylated regions (DMRs)) that allow differentiation between nevi and the primary tumors that do not have classical oncogenic mutations (triple negative CM and some UM with disomy 3). These tumors cannot always be reliably distinguished from nevi based on genetic, histologic, or clinical markers. Because both choroidal and cutaneous melanoma metastases lack metastasis-specific mutations, we will investigate whether certain epigenetic alterations, in addition to those already found in primary melanomas, are associated with metastasis formation and whether these alterations and thus the mechanisms are similar in ocular and cutaneous melanomas. The functional significance of the genes associated with the identified DMRs may shed light on the mechanisms involved in melanoma development.