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

黑色素瘤被认为是由黑素细胞祖细胞（主要是）体细胞突变引起的。值得注意的是，不同组织（如皮肤或眼睛）发生的黑色素瘤不仅临床不同，而且具有不同的突变模式，从而代表不同的肿瘤实体。我们假设皮肤和脉络膜中的黑素细胞前体已经是不同的细胞类型，因此DNA甲基化模式的特征不同。痣可以由黑色素细胞克隆扩增产生，并且通常已经携带某些特定黑色素瘤类型的致癌突变（GNAQ/11或BRAF）。因此它们被认为是葡萄膜（UM）和皮肤黑色素瘤（CM）癌变的良性中间阶段。皮肤和眼睛的黑素细胞和痣之间的差异的性质和程度尚不清楚。在这里，我们的目标是对黑色素细胞、痣、原发性黑色素瘤和皮肤和葡萄膜黑色素细胞谱系转移的常染色体CpGs进行全基因组DNA甲基化分析。甲基化分析在单个CpGs水平上使用em -测序进行。使用已建立的算法，我们将确定表现出动态组织或阶段依赖性甲基化差异的区域。通过比较皮肤和葡萄膜黑色素细胞的甲基化模式，我们旨在确定皮肤和脉络膜中黑色素细胞是否不同以及在哪些方面不同。由于肿瘤中保留了起源细胞的大部分甲基化模式，因此可以假设鉴定出的差异也存在于原发肿瘤中，从而导致了两种肿瘤实体之间的差异。此外，我们的目标是确定表观遗传标记（差异甲基化区域（DMRs）），这些标记允许痣和原发肿瘤之间的区分，而原发肿瘤没有经典的致癌突变（三阴性CM和一些具有二体3的UM）。基于遗传、组织学或临床标记，这些肿瘤不能总是可靠地与痣区分开。由于脉络膜和皮肤黑色素瘤转移都缺乏转移特异性突变，我们将研究除原发性黑色素瘤中发现的外，某些表观遗传改变是否与转移形成有关，以及这些改变及其机制是否在眼部和皮肤黑色素瘤中相似。与确定的DMRs相关的基因的功能意义可能会揭示黑色素瘤发展的机制。

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.