Genes regulated by DNA methylation are involved in distinct phenotypes during melanoma progression and are prognostic factors for patients.
Genes regulated by DNA methylation are involved in distinct phenotypes during melanoma progression and are prognostic factors for patients.
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DOI：
10.1002/1878-0261.13185
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发表时间：
2022-05
影响因子：
6.6
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中科院分区：
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除了突变，表观遗传学改变是恶性转化和肿瘤进展的重要贡献者。这项工作的目的是确定表观遗传事件，其中启动子或基因体DNA甲基化诱导基因表达的变化，驱动黑素细胞恶性转化和转移。我们以前开发了一个线性小鼠模型的黑色素瘤的进展，包括自发永生化的黑色素细胞，癌前黑色素细胞，非转移性致瘤，和转移性细胞系。在这里，通过对甲基化组和转录组数据的综合分析，我们确定了黑色素瘤进展的早期、中期和晚期阶段启动子和/或基因体DNA甲基化改变与基因表达之间的关系。我们鉴定了腺苷酸环化酶3型（Adcy 3）和肌醇多磷酸4-磷酸酶II型（Inpp 4 b），它们分别影响肿瘤生长和转移潜力。重要的是，在这种黑色素瘤进展的鼠模型中发现的基因表达和DNA甲基化谱与来自基于大群体的原发性黑色素瘤队列的可用临床数据相关，揭示了潜在的预后标志物。与异常基因表达相关的表观遗传学改变是恶性转化和黑色素瘤进展的重要调节因子。在这里，我们整合了来自小鼠黑色素瘤进展线性模型的转录组和甲基化组数据，并鉴定了诱导与黑色素细胞转化和转移相关的基因表达变化的启动子和/或基因体DNA甲基化谱。我们将Adcy 3和Inpp 4 b定义为体内转移的关键调节因子，并观察到所鉴定的谱/基因与患者存活的相关性，从而证明它们作为预后标志物的潜在用途。
In addition to mutations, epigenetic alterations are important contributors to malignant transformation and tumor progression. The aim of this work was to identify epigenetic events in which promoter or gene body DNA methylation induces gene expression changes that drive melanocyte malignant transformation and metastasis. We previously developed a linear mouse model of melanoma progression consisting of spontaneously immortalized melanocytes, premalignant melanocytes, a nonmetastatic tumorigenic, and a metastatic cell line. Here, through the integrative analysis of methylome and transcriptome data, we identified the relationship between promoter and/or gene body DNA methylation alterations and gene expression in early, intermediate, and late stages of melanoma progression. We identified adenylate cyclase type 3 (Adcy3) and inositol polyphosphate 4‐phosphatase type II (Inpp4b), which affect tumor growth and metastatic potential, respectively. Importantly, the gene expression and DNA methylation profiles found in this murine model of melanoma progression were correlated with available clinical data from large population‐based primary melanoma cohorts, revealing potential prognostic markers. Epigenetic alterations related to aberrant gene expression are important regulators of malignant transformation and melanoma progression. Here, we integrated transcriptome and methylome data from a linear model of murine melanoma progression and identified promoter and/or gene body DNA methylation profiles that induced gene expression changes related to melanocyte transformation and metastasis. We defined Adcy3 and Inpp4b as key regulators of metastasis in vivo and observed a correlation of the identified profiles/genes to patient survival, thus demonstrating their potential use as prognostic markers.