Department of Medical and Molecular Genetics, King's College London, London, SE1 9RT, UK.
Comprehensive Cancer Centre, King's College London, London, SE5 8AF, UK.
Clin Epigenetics. 2023 Dec 20;15(1):196. doi: 10.1186/s13148-023-01598-3.
Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumours. Pathogenic variants have been identified in more than 15 susceptibility genes; associated tumours are grouped into three Clusters, reinforced by their transcriptional profiles. Cluster 1A PPGLs have pathogenic variants affecting enzymes of the tricarboxylic acid cycle, including succinate dehydrogenase. Within inherited PPGLs, these are the most common. PPGL tumours are known to undergo epigenetic reprograming, and here, we report on global histone post-translational modifications and DNA methylation levels, alongside clinical phenotypes.
Out of the 25 histone post-translational modifications examined, Cluster 1A PPGLs were distinguished from other tumours by a decrease in hyper-acetylated peptides and an increase in H3K4me2. DNA methylation was compared between tumours from individuals who developed metastatic disease versus those that did not. The majority of differentially methylated sites identified tended to be completely methylated or unmethylated in non-metastatic tumours, with low inter-sample variance. Metastatic tumours by contrast consistently had an intermediate DNA methylation state, including the ephrin receptor EPHA4 and its ligand EFNA3. Gene expression analyses performed to identify genes involved in metastatic tumour behaviour pin-pointed a number of genes previously described as mis-regulated in Cluster 1A tumours, as well as highlighting the tumour suppressor RGS22 and the pituitary tumour-transforming gene PTTG1.
Combined transcriptomic and DNA methylation analyses revealed aberrant pathways, including ones that could be implicated in metastatic phenotypes and, for the first time, we report a decrease in hyper-acetylated histone marks in Cluster 1 PPGLs.
嗜铬细胞瘤和副神经节瘤（PPGLs）是罕见的神经内分泌肿瘤。已经在超过 15 个易感性基因中发现了致病变异；相关肿瘤分为三个簇，通过其转录谱得到加强。1A 簇 PPGLs 具有影响三羧酸循环酶的致病变异，包括琥珀酸脱氢酶。在遗传性 PPGLs 中，这些是最常见的。已知 PPGL 肿瘤经历表观遗传重编程，在这里，我们报告了全局组蛋白翻译后修饰和 DNA 甲基化水平，以及临床表型。
在检查的 25 种组蛋白翻译后修饰中，1A 簇 PPGLs 与其他肿瘤通过减少超乙酰化肽和增加 H3K4me2 来区分。比较了个体中发生转移疾病的肿瘤与未发生转移疾病的肿瘤之间的 DNA 甲基化。大多数鉴定的差异甲基化位点在非转移性肿瘤中倾向于完全甲基化或非甲基化，样本间差异较小。相比之下，转移性肿瘤始终具有中间 DNA 甲基化状态，包括 Eph 受体 EPHA4 及其配体 EFNA3。为鉴定参与转移性肿瘤行为的基因而进行的基因表达分析确定了一些先前描述为 1A 簇肿瘤中失调的基因，并突出了肿瘤抑制基因 RGS22 和垂体肿瘤转化基因 PTTG1。
联合转录组和 DNA 甲基化分析揭示了异常途径，包括可能与转移表型有关的途径，并且我们首次报告了 1 簇 PPGLs 中组蛋白超乙酰化标记的减少。
