文章：

原发性葡萄膜黑色素瘤全基因组甲基化模式：开发MethylSig-UM表观基因组预后特征以优化患者分层

Genome-Wide Methylation Patterns in Primary Uveal Melanoma: Development of MethylSig-UM, an Epigenomic Prognostic Signature to Improve Patient Stratification

原文发布日期：25 July 2024

DOI: 10.3390/cancers16152650

类型: Article

开放获取: 是

英文摘要：

Despite studies highlighting the prognostic utility of DNA methylation in primary uveal melanoma (pUM), it has not been translated into a clinically useful tool. We sought to define a methylation signature to identify newly diagnosed individuals at high risk for developing metastasis. Methylation profiling was performed on 41 patients with pUM with stage T2–T4 and at least three years of follow-up using the Illumina Infinium HumanMethylation450K BeadChip (N = 24) and the EPIC BeadChip (N = 17). Findings were validated in the TCGA cohort with known metastatic outcome (N = 69). Differentially methylated probes were identified in patients who developed metastasis. Unsupervised consensus clustering revealed three epigenomic subtypes associated with metastasis. To identify a prognostic signature, recursive feature elimination and random forest models were utilized within repeated cross-validation iterations. The 250 most commonly selected probes comprised the final signature, named MethylSig-UM. MethylSig-UM could distinguish individuals with pUM at diagnosis who develop future metastasis with an area under the curve of ~81% in the independent validation cohort, and remained significant in Cox proportional hazard models when combined with clinical features and established genomic biomarkers. Altered expression of immune-modulating genes were detected in MethylSig-UM positive tumors, providing clues for pUM resistance to immunotherapy. The MethylSig-UM model is available to enable additional validation in larger cohort sizes including T1 tumors.

摘要翻译： 

尽管已有研究强调DNA甲基化在原发性葡萄膜黑色素瘤（pUM）中的预后价值，但其尚未转化为临床实用工具。本研究旨在定义一种甲基化特征，以识别新诊断且具有高转移风险的个体。我们使用Illumina Infinium HumanMethylation450K芯片（N = 24）和EPIC芯片（N = 17）对41例T2–T4期pUM患者进行了甲基化分析，所有患者均具有至少三年的随访数据。研究结果在已知转移结局的TCGA队列（N = 69）中进行了验证。在发生转移的患者中识别出差异甲基化探针。无监督一致性聚类揭示了三种与转移相关的表观基因组亚型。为确定预后特征，我们在重复交叉验证迭代中采用递归特征消除和随机森林模型。最终筛选出的250个最常被选中的探针构成了名为MethylSig-UM的最终特征。在独立验证队列中，MethylSig-UM能够区分诊断时已发生未来转移的pUM个体，曲线下面积约为81%，且在与临床特征及已确立的基因组生物标志物结合后，在Cox比例风险模型中仍保持显著意义。在MethylSig-UM阳性肿瘤中检测到免疫调节基因的表达改变，为pUM对免疫治疗的抵抗提供了线索。MethylSig-UM模型可用于在更大规模队列（包括T1期肿瘤）中进行进一步验证。

原文链接：

Genome-Wide Methylation Patterns in Primary Uveal Melanoma: Development of MethylSig-UM, an Epigenomic Prognostic Signature to Improve Patient Stratification