Integrative multi-omics reveals two biologically distinct groups of pilocytic astrocytoma

被引:1
|
作者
Picard, Daniel [1 ,2 ,3 ,4 ]
Felsberg, Joerg [2 ,4 ]
Langini, Maike [1 ,2 ,5 ,6 ]
Stachura, Pawel [1 ,2 ,7 ]
Qin, Nan [1 ,2 ,3 ,4 ]
Macas, Jadranka [8 ,9 ,10 ]
Reiss, Yvonne [8 ,9 ,10 ]
Bartl, Jasmin [1 ,2 ,3 ,4 ]
Selt, Florian [11 ,12 ,13 ,14 ]
Sigaud, Romain [11 ,12 ,13 ,14 ]
Meyer, Frauke-D. [1 ,2 ,3 ,4 ]
Stefanski, Anja [5 ,6 ]
Stuehler, Kai [5 ,6 ]
Roque, Lucia [15 ]
Roque, Rafael [16 ]
Pandyra, Aleksandra A. [1 ,2 ,17 ,18 ]
Brozou, Triantafyllia [1 ,2 ]
Knobbe-Thomsen, Christiane [2 ,4 ]
Plate, Karl H. [8 ,9 ,10 ]
Roesch, Alexander [3 ,19 ,20 ]
Milde, Till [11 ,12 ,13 ,14 ,21 ]
Reifenberger, Guido [2 ,3 ,4 ]
Leprivier, Gabriel [2 ,4 ]
Faria, Claudia C. [22 ,23 ]
Remke, Marc [1 ,2 ,3 ,4 ]
机构
[1] Heinrich Heine Univ, Med Fac, Dept Pediat Oncol Hematol & Clin Immunol, Dusseldorf, Germany
[2] Heinrich Heine Univ, Univ Hosp Dusseldorf, Dusseldorf, Germany
[3] German Canc Consortium DKTK, Partner Site Essen Dusseldorf, Dusseldorf, Germany
[4] Heinrich Heine Univ, Inst Neuropathol, Med Fac, Dusseldorf, Germany
[5] Heinrich Heine Univ Dusseldorf, Biol & Med Res Ctr BMFZ, Mol Prote Lab, Dusseldorf, Germany
[6] Heinrich Heine Univ, Med Fac, Inst Mol Med 1, Dusseldorf, Germany
[7] Heinrich Heine Univ, Med Fac, Inst Mol Med 2, Dusseldorf, Germany
[8] Univ Hosp Frankfurt, Inst Neurol, Edinger Inst, Frankfurt, Germany
[9] German Canc Consortium DKTK, Partner Site Frankfurt Mainz, Frankfurt, Germany
[10] Frankfurt Canc Inst, Frankfurt, Germany
[11] Hopp Childrens Canc Ctr Heidelberg KiTZ, Heidelberg, Germany
[12] German Canc Res Ctr, Clin Cooperat Unit Pediat Oncol, Heidelberg, Germany
[13] German Canc Consortium DKTK, Heidelberg, Germany
[14] Heidelberg Univ Hosp, Dept Pediat Hematol & Oncol, KiTZ Clin Trial Unit ZIPO, Heidelberg, Germany
[15] IPOLFG, Portuguese Canc Inst, Unidade Invest Patobiol Mol UIPM, Lisbon, Portugal
[16] Ctr Hosp Univ Lisboa Norte CHULN, Hosp Santa Maria, Neurol Dept, Lab Neuropathol, Lisbon, Portugal
[17] Univ Hosp Bonn, Inst Clin Chem & Clin Pharmacol, Bonn, Germany
[18] German Ctr Infect Res DZIF, Partner Site Bonn Cologne, Bonn, Germany
[19] Univ Duisburg Essen, Univ Hosp Essen, West German Canc Ctr, Dept Dermatol, Essen, Germany
[20] Univ Duisburg Essen, Ctr Med Biotechnol ZMB, Essen, Germany
[21] Natl Ctr Tumor Dis NCT, Heidelberg, Germany
[22] Univ Lisbon, Fac Med, Inst Med Mol Joao Lobo Antunes, Lisbon, Portugal
[23] Ctr Hosp Univ Lisboa Norte CHULN, Hosp Santa Maria, Dept Neurosurg, Lisbon, Portugal
关键词
Pilocytic astrocytoma; Intertumoral heterogeneity; Integrative multi-omics; MAPK PATHWAY ACTIVATION; CENTRAL-NERVOUS-SYSTEM; PROTEOGENOMIC CHARACTERIZATION; EXPRESSION; CLASSIFICATION; MUTATIONS; HETEROGENEITY; DUPLICATION; METHYLATION; CEREBELLAR;
D O I
10.1007/s00401-023-02626-5
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
Pilocytic astrocytoma (PA), the most common pediatric brain tumor, is driven by aberrant mitogen-activated protein kinase signaling most commonly caused by BRAF gene fusions or activating mutations. While 5-year overall survival rates exceed 95%, tumor recurrence or progression constitutes a major clinical challenge in incompletely resected tumors. Here, we used similarity network fusion (SNF) analysis in an integrative multi-omics approach employing RNA transcriptomic and mass spectrometry-based proteomic profiling to molecularly characterize PA tissue samples from 62 patients. Thereby, we uncovered that PAs segregated into two molecularly distinct groups, namely, Group 1 and Group 2, which were validated in three non-overlapping cohorts. Patients with Group 1 tumors were significantly younger and showed worse progression-free survival compared to patients with group 2 tumors. Ingenuity pathways analysis (IPA) and gene set enrichment analysis (GSEA) revealed that Group 1 tumors were enriched for immune response pathways, such as interferon signaling, while Group 2 tumors showed enrichment for action potential and neurotransmitter signaling pathways. Analysis of immune cell-related gene signatures showed an enrichment of infiltrating T Cells in Group 1 versus Group 2 tumors. Taken together, integrative multi-omics of PA identified biologically distinct and prognostically relevant tumor groups that may improve risk stratification of this single pathway driven tumor type.
引用
收藏
页码:551 / 564
页数:14
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