Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex.
Distinct DNA Methylation Patterns of Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex.
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DOI：
10.1007/s10571-021-01157-5
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发表时间：
2022-11
影响因子：
4
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中科院分区：
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多发性硬化症（TSC）是由TSC 1或TSC 2基因突变引起的单基因疾病，TSC 1或TSC 2基因是雷帕霉素复合物途径的机制靶点的两个关键调节因子。从表型上看，这会导致包括大脑在内的多个器官中错构瘤的生长和形成。室管膜下巨细胞星形细胞瘤（SEGA）是一种低度恶性的脑肿瘤，通常与TSC相关。最近，基因表达研究提供的证据表明，免疫系统，MAPK途径和细胞外基质组织在SEGA的发展中发挥重要作用。然而，SEGA中基因表达变化背后的确切机制在很大程度上仍然是未知的，这为DNA甲基化提供了潜在的作用。我们使用Illumina Infinium HumanMethylation 450 BeadChip研究了SEGA的甲基化谱（SEGA n = 42，脑室周围对照n = 8）。SEGA甲基化谱针对适应性免疫系统、T细胞活化、白细胞介导的免疫、细胞外结构组织和ERK 1和ERK 2级联而富集。更有趣的是，我们在SEGA甲基化数据中确定了两个亚组，并表明这两个亚组之间的差异表达基因与MAPK级联反应和适应性免疫反应有关。总的来说，这项研究表明，免疫系统，MAPK途径和细胞外基质组织也受到DNA甲基化水平的影响，这表明DNA水平的治疗干预可能对SEGA中的这些特定途径有用。此外，我们确定了SEGA中的两个亚组，它们似乎是由适应性免疫应答和MAPK通路的变化驱动的，并且可能具有关于靶向治疗应答的预测信息。在线版本包含补充材料，可通过10.1007/s10571-021-01157-5获得。
Tuberous sclerosis complex (TSC) is a monogenic disorder caused by mutations in either the TSC1 or TSC2 gene, two key regulators of the mechanistic target of the rapamycin complex pathway. Phenotypically, this leads to growth and formation of hamartomas in several organs, including the brain. Subependymal giant cell astrocytomas (SEGAs) are low-grade brain tumors commonly associated with TSC. Recently, gene expression studies provided evidence that the immune system, the MAPK pathway and extracellular matrix organization play an important role in SEGA development. However, the precise mechanisms behind the gene expression changes in SEGA are still largely unknown, providing a potential role for DNA methylation. We investigated the methylation profile of SEGAs using the Illumina Infinium HumanMethylation450 BeadChip (SEGAs n = 42, periventricular control n = 8). The SEGA methylation profile was enriched for the adaptive immune system, T cell activation, leukocyte mediated immunity, extracellular structure organization and the ERK1 & ERK2 cascade. More interestingly, we identified two subgroups in the SEGA methylation data and show that the differentially expressed genes between the two subgroups are related to the MAPK cascade and adaptive immune response. Overall, this study shows that the immune system, the MAPK pathway and extracellular matrix organization are also affected on DNA methylation level, suggesting that therapeutic intervention on DNA level could be useful for these specific pathways in SEGA. Moreover, we identified two subgroups in SEGA that seem to be driven by changes in the adaptive immune response and MAPK pathway and could potentially hold predictive information on target treatment response. The online version contains supplementary material available at 10.1007/s10571-021-01157-5.
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影响因子：
64.8
作者：
Capper D;Jones DTW;Sill M;Hovestadt V;Schrimpf D;Sturm D;Koelsche C;Sahm F;Chavez L;Reuss DE;Kratz A;Wefers AK;Huang K;Pajtler KW;Schweizer L;Stichel D;Olar A;Engel NW;Lindenberg K;Harter PN;Braczynski AK;Plate KH;Dohmen H;Garvalov BK;Coras R;Hölsken A;Hewer E;Bewerunge-Hudler M;Schick M;Fischer R;Beschorner R;Schittenhelm J;Staszewski O;Wani K;Varlet P;Pages M;Temming P;Lohmann D;Selt F;Witt H;Milde T;Witt O;Aronica E;Giangaspero F;Rushing E;Scheurlen W;Geisenberger C;Rodriguez FJ;Becker A;Preusser M;Haberler C;Bjerkvig R;Cryan J;Farrell M;Deckert M;Hench J;Frank S;Serrano J;Kannan K;Tsirigos A;Brück W;Hofer S;Brehmer S;Seiz-Rosenhagen M;Hänggi D;Hans V;Rozsnoki S;Hansford JR;Kohlhof P;Kristensen BW;Lechner M;Lopes B;Mawrin C;Ketter R;Kulozik A;Khatib Z;Heppner F;Koch A;Jouvet A;Keohane C;Mühleisen H;Mueller W;Pohl U;Prinz M;Benner A;Zapatka M;Gottardo NG;Driever PH;Kramm CM;Müller HL;Rutkowski S;von Hoff K;Frühwald MC;Gnekow A;Fleischhack G;Tippelt S;Calaminus G;Monoranu CM;Perry A;Jones C;Jacques TS;Radlwimmer B;Gessi M;Pietsch T;Schramm J;Schackert G;Westphal M;Reifenberger G;Wesseling P;Weller M;Collins VP;Blümcke I;Bendszus M;Debus J;Huang A;Jabado N;Northcott PA;Paulus W;Gajjar A;Robinson GW;Taylor MD;Jaunmuktane Z;Ryzhova M;Platten M;Unterberg A;Wick W;Karajannis MA;Mittelbronn M;Acker T;Hartmann C;Aldape K;Schüller U;Buslei R;Lichter P;Kool M;Herold-Mende C;Ellison DW;Hasselblatt M;Snuderl M;Brandner S;Korshunov A;von Deimling A;Pfister SM
通讯作者：
Pfister SM
影响因子：
8.4
作者：
Jiang, WG;Sampson, J;Mansel, RE
通讯作者：
Mansel, RE
影响因子：
2.2
作者：
Boer, K.;Jansen, F.;Aronica, E.
通讯作者：
Aronica, E.
影响因子：
16
作者：
Dibble, Christian C.;Elis, Winfried;Menon, Suchithra;Qin, Wei;Klekota, Justin;Asara, John M.;Finan, Peter M.;Kwiatkowski, David J.;Murphy, Leon O.;Manning, Brendan D.
通讯作者：
Manning, Brendan D.
影响因子：
10.5
作者：
Inoki, K;Li, Y;Guan, KL
通讯作者：
Guan, KL