A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide.
A comprehensive characterisation of phaeochromocytoma and paraganglioma tumours through histone protein profiling, DNA methylation and transcriptomic analysis genome wide.
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DOI：
10.1186/s13148-023-01598-3
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发表时间：
2023-12-20
影响因子：
5.7
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中科院分区：
文献类型：
--
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嗜铬细胞瘤和副神经节瘤是罕见的神经内分泌肿瘤。已在超过15个易感基因中鉴定出致病性变体;相关肿瘤被分为三个簇，并通过其转录谱得到加强。簇1A PPGL具有影响三羧酸循环的酶（包括琥珀酸脱氢酶）的致病性变体。在遗传性PPGL中，这些是最常见的。已知PPGL肿瘤会经历表观遗传重编程，在这里，我们报告了全球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，簇1A PPGL与其他肿瘤的区别在于超乙酰化肽的减少和H3 K4 me 2的增加。DNA甲基化在发生转移性疾病的个体与未发生转移性疾病的个体的肿瘤之间进行了比较。在非转移性肿瘤中，大多数差异甲基化位点倾向于完全甲基化或未甲基化，样本间方差较低。相比之下，转移性肿瘤始终具有中间DNA甲基化状态，包括肝配蛋白受体EPHA 4及其配体EFNA 3。进行基因表达分析，以确定参与转移性肿瘤行为的基因，确定了一些先前描述为在1A类肿瘤中失调的基因，并突出了肿瘤抑制基因RGS 22和垂体肿瘤转化基因PTTG 1。联合转录组学和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，我们首次报告了簇1 PPGL中超乙酰化组蛋白标记的减少。在线版本包含补充材料，可通过10.1186/s13148-023-01598-3获得。
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. The online version contains supplementary material available at 10.1186/s13148-023-01598-3.
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影响因子：
50.3
作者：
Fishbein L;Leshchiner I;Walter V;Danilova L;Robertson AG;Johnson AR;Lichtenberg TM;Murray BA;Ghayee HK;Else T;Ling S;Jefferys SR;de Cubas AA;Wenz B;Korpershoek E;Amelio AL;Makowski L;Rathmell WK;Gimenez-Roqueplo AP;Giordano TJ;Asa SL;Tischler AS;Cancer Genome Atlas Research Network;Pacak K;Nathanson KL;Wilkerson MD
通讯作者：
Wilkerson MD
影响因子：
14.9
作者：
The Gene Ontology Consortium
通讯作者：
The Gene Ontology Consortium
影响因子：
12.3
作者：
Gentleman RC;Carey VJ;Bates DM;Bolstad B;Dettling M;Dudoit S;Ellis B;Gautier L;Ge Y;Gentry J;Hornik K;Hothorn T;Huber W;Iacus S;Irizarry R;Leisch F;Li C;Maechler M;Rossini AJ;Sawitzki G;Smith C;Smyth G;Tierney L;Yang JY;Zhang J
通讯作者：
Zhang J
影响因子：
11.5
作者：
Geli, Janos;Kiss, Nimrod;Larsson, Catharina
通讯作者：
Larsson, Catharina
影响因子：
8
作者：
Gómez-Maldonado L;Tiana M;Roche O;Prado-Cabrero A;Jensen L;Fernandez-Barral A;Guijarro-Muñoz I;Favaro E;Moreno-Bueno G;Sanz L;Aragones J;Harris A;Volpert O;Jimenez B;del Peso L
通讯作者：
del Peso L