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引起的（主要是）体细胞突变的结果。值得注意的是，在不同组织（例如皮肤或眼睛）中产生的黑素瘤不仅在临床上不同，而且特征在于不同的突变模式，因此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，因此通过特征性DNA甲基化模式而不同。痣可以通过克隆扩增从黑素细胞产生，并且通常已经携带特定黑色素瘤类型的一些致癌突变（GNAQ/11或BRAF）。因此，它们被认为是葡萄膜（UM）和皮肤黑色素瘤（CM）癌变过程中的良性中间阶段。黑色素细胞和皮肤及眼睛痣之间的差异的性质和程度还不清楚。在这里，我们的目标是进行全基因组DNA甲基化分析的常染色体CpG在黑色素细胞，痣，原发性黑色素瘤，皮肤和葡萄膜黑色素细胞谱系的转移。使用EM测序在单个CpG水平进行甲基化分析。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素细胞的甲基化模式，我们的目的是确定是否以及在哪些方面黑素细胞在皮肤和脉络膜不同。由于起源细胞的大部分甲基化模式保留在肿瘤中，因此可以假设所鉴定的差异也存在于原发性肿瘤中，从而导致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（DMR）），允许痣和原发性肿瘤之间的区别，没有经典的致癌突变（三阴性CM和一些UM与二体性3）。这些肿瘤不能总是可靠地区分痣的基础上遗传，组织学，或临床标志物。由于脉络膜和皮肤黑色素瘤转移缺乏转移特异性突变，我们将研究除了原发性黑色素瘤中已经发现的外，某些表观遗传学改变是否与转移形成相关，以及这些改变和机制是否在眼部和皮肤黑色素瘤中相似。与所鉴定的DMR相关的基因的功能意义可能揭示黑色素瘤发展中所涉及的机制。

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.