Comprehensive DNA Methylation Profiling of Medullary Thyroid Carcinoma: Molecular Classification, Potential Therapeutic Target, and Classifier System
Comprehensive DNA Methylation Profiling of Medullary Thyroid Carcinoma: Molecular Classification, Potential Therapeutic Target, and Classifier System
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DOI：
10.1158/1078-0432.ccr-23-2142
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发表时间：
2024-01-01
影响因子：
11.5
通讯作者：
Wang，Yu
中科院分区：
文献类型：
--
作者：
Shen，Cenkai;Shi，Xiao;Wang，Yu
甲状腺髓样癌（MTC）由于其特殊的细胞来源而具有不同于其他甲状腺癌的生物学背景。这种异质性和罕见的肿瘤具有高度的晚期疾病患病率，因此解决有限的治疗选择和加强复杂的临床管理至关重要。鉴于甲基化信息的高度临床可及性，我们构建了迄今为止最大的MTC甲基化队列。全面的研究过程纳入机器学习，统计分析，andin vitroexperiments.ResultsOur的研究开创了一个三类聚类系统的风险分层，表现出明显的表观基因组异质性的识别。MTC-B中升高的总体甲基化状态，结合MTC-A和MTC-C显示的低甲基化位点的“互斥性”，独特地表征了MTC特异性甲基化模式。结合转录组，我们进一步描绘了这三个集群的特征，以审查生物学特性。我们的研究强调了几个MTC特异性异常DNA甲基化事件，发现NNAT表达在预后不良的MTC-C中显著降低，其启动子区域与上调的差异甲基化区域重叠，体外实验进一步证实了NNAT的治疗潜力。此外，我们建立了一个弹性网络逻辑回归模型，具有相对较高的AUC，包括68探针，用于未来的验证和系统的临床应用。ConclusionsConducting研究的疾病发病率低，带来了重大挑战，我们提供了一个强大的资源和全面的研究框架，以协助正在进行的MTC病例纳入，并促进其分子生物学特征的深入解剖。
PurposeMedullary thyroid carcinoma (MTC) presents a distinct biological context from other thyroid cancers due to its specific cellular origin. This heterogeneous and rare tumor has a high prevalence of advanced diseases, making it crucial to address the limited therapeutic options and enhance complex clinical management. Given the high clinical accessibility of methylation information, we construct the largest MTC methylation cohort to date.Experimental DesignSeventy-eight fresh-frozen MTC samples constituted our methylation cohort. The comprehensive study process incorporated machine learning, statistical analysis, andin vitroexperiments.ResultsOur study pioneered the identification of a three-class clustering system for risk stratification, exhibiting pronounced epigenomic heterogeneity. The elevated overall methylation status in MTC-B, combined with the “mutual exclusivity” of hypomethylated sites displayed by MTC-A and MTC-C, distinctively characterized the MTC-specific methylation pattern. Integrating with the transcriptome, we further depicted the features of these three clusters to scrutinize biological properties. Several MTC-specific aberrant DNA methylation events were emphasized in our study.NNATexpression was found to be notably reduced in poor-prognostic MTC-C, with its promoter region overlapping with an upregulated differentially methylated region.In vitroexperiments further affirmedNNAT's therapeutic potential. Moreover, we built an elastic-net logistic regression model with a relatively high AUC encompassing 68 probes, intended for future validation and systematic clinical application.ConclusionsConducting research on diseases with low incidence poses significant challenges, and we provide a robust resource and comprehensive research framework to assist in ongoing MTC case inclusion and facilitate in-depth dissection of its molecular biological features.