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

剖析黑色素细胞向皮肤和葡萄膜的各种黑色素细胞病变转变过程中产生的 DNA 甲基化变化。

• 批准号: 497791196
• 负责人: Privatdozent Dr. Klaus Georg Griewank
• 金额: --
• 依托单位: Institut für Humangenetik
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/497791196?language=en
• 关键词: Dissecting; DNA; methylation; changes; arising

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.

黑色素瘤被认为是由于(大多数)体细胞突变而产生的黑素细胞前体细胞。值得注意的是，发生在不同组织(如皮肤或眼睛)的黑色素瘤不仅临床上不同，而且具有不同的突变模式，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，因此具有不同的DNA甲基化模式。色素痣可以由黑素细胞克隆扩增而来，通常已经携带了某些特定黑色素瘤类型特有的致癌突变(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色素痣之间的区别的性质和程度还不是很清楚。在这里，我们的目标是对黑素细胞、色素痣、原发黑色素瘤以及皮肤和葡萄膜黑素细胞系转移瘤中的常染色体CPGS进行全基因组DNA甲基化分析。甲基化分析是在单个CPGS的水平上使用EM测序进行的。使用已建立的算法，我们将确定呈现动态组织或阶段相关甲基化差异的区域。通过比较皮肤和葡萄膜黑素细胞的甲基化模式，我们的目标是确定黑素细胞在皮肤和脉络膜中是否不同以及在哪些方面不同。由于大部分起源细胞的甲基化模式被保留在肿瘤中，可以假设已发现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(DMR))，以区分Nevi和没有经典致癌突变的原发肿瘤(三阴性CM和一些具有二体3的UM)。根据遗传、组织学或临床标记物，这些肿瘤并不总是可靠地与痣区分开来。由于脉络膜黑色素瘤和皮肤黑色素瘤的转移都缺乏转移特异性突变，我们将调查除了已在原发黑色素瘤中发现的那些外，某些表观遗传学改变是否与转移形成有关，以及这些改变是否与眼部和皮肤黑色素瘤的机制相似。与已鉴定的DMRS相关的基因的功能意义可能有助于阐明与黑色素瘤发展有关的机制。