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000136677 1001_ $$00000-0003-4925-7600$$aDeng, Maximilian Y$$b0$$eFirst author
000136677 245__ $$aMolecularly defined diffuse leptomeningeal glioneuronal tumor (DLGNT) comprises two subgroups with distinct clinical and genetic features.
000136677 260__ $$aBerlin$$bSpringer$$c2018
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000136677 520__ $$aDiffuse leptomeningeal glioneuronal tumors (DLGNT) represent rare CNS neoplasms which have been included in the 2016 update of the WHO classification. The wide spectrum of histopathological and radiological features can make this enigmatic tumor entity difficult to diagnose. In recent years, large-scale genomic and epigenomic analyses have afforded insight into key genetic alterations occurring in multiple types of brain tumors and provide unbiased, complementary tools to improve diagnostic accuracy. Through genome-wide DNA methylation screening of > 25,000 tumors, we discovered a molecularly distinct class comprising 30 tumors, mostly diagnosed histologically as DLGNTs. Copy-number profiles derived from the methylation arrays revealed unifying characteristics, including loss of chromosomal arm 1p in all cases. Furthermore, this molecular DLGNT class can be subdivided into two subgroups [DLGNT methylation class (MC)-1 and DLGNT methylation class (MC)-2], with all DLGNT-MC-2 additionally displaying a gain of chromosomal arm 1q. Co-deletion of 1p/19q, commonly seen in IDH-mutant oligodendroglioma, was frequently observed in DLGNT, especially in DLGNT-MC-1 cases. Both subgroups also had recurrent genetic alterations leading to an aberrant MAPK/ERK pathway, with KIAA1549:BRAF fusion being the most frequent event. Other alterations included fusions of NTRK1/2/3 and TRIM33:RAF1, adding up to an MAPK/ERK pathway activation identified in 80% of cases. In the DLGNT-MC-1 group, age at diagnosis was significantly lower (median 5 vs 14 years, p < 0.01) and clinical course less aggressive (5-year OS 100, vs 43% in DLGNT-MC-2). Our study proposes an additional molecular layer to the current histopathological classification of DLGNT, of particular use for cases without typical morphological or radiological characteristics, such as diffuse growth and radiologic leptomeningeal dissemination. Recurrent 1p deletion and MAPK/ERK pathway activation represent diagnostic biomarkers and therapeutic targets, respectively-laying the foundation for future clinical trials with, e.g., MEK inhibitors that may improve the clinical outcome of patients with DLGNT.
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000136677 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b1$$udkfz
000136677 7001_ $$aChiang, Jason$$b2
000136677 7001_ $$aSchittenhelm, Jens$$b3
000136677 7001_ $$aEbinger, Martin$$b4
000136677 7001_ $$aSchuhmann, Martin U$$b5
000136677 7001_ $$aMonoranu, Camelia-Maria$$b6
000136677 7001_ $$0P:(DE-He78)0be2f86573954f87e97f8a4dbb05cb0f$$aMilde, Till$$b7$$udkfz
000136677 7001_ $$0P:(DE-He78)adf0bc22f6c87d09ddb939645a7870ed$$aWittmann, Andrea$$b8$$udkfz
000136677 7001_ $$aHartmann, Christian$$b9
000136677 7001_ $$aSommer, Clemens$$b10
000136677 7001_ $$aPaulus, Werner$$b11
000136677 7001_ $$aGärtner, Jutta$$b12
000136677 7001_ $$aBrück, Wolfgang$$b13
000136677 7001_ $$aRüdiger, Thomas$$b14
000136677 7001_ $$aLeipold, Alfred$$b15
000136677 7001_ $$aJaunmuktane, Zane$$b16
000136677 7001_ $$aBrandner, Sebastian$$b17
000136677 7001_ $$aGiangaspero, Felice$$b18
000136677 7001_ $$aNozza, Paolo$$b19
000136677 7001_ $$aMora, Jaume$$b20
000136677 7001_ $$aMorales la Madrid, Andres$$b21
000136677 7001_ $$aCruz Martinez, Ofelia$$b22
000136677 7001_ $$aHansford, Jordan R$$b23
000136677 7001_ $$aPietsch, Torsten$$b24
000136677 7001_ $$aTietze, Anna$$b25
000136677 7001_ $$aHernáiz-Driever, Pablo$$b26
000136677 7001_ $$aStoler, Iris$$b27
000136677 7001_ $$aCapper, David$$b28
000136677 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b29$$udkfz
000136677 7001_ $$aEllison, David W$$b30
000136677 7001_ $$0P:(DE-He78)a8a10626a848d31e70cfd96a133cc144$$avon Deimling, Andreas$$b31$$udkfz
000136677 7001_ $$0P:(DE-He78)f746aa965c4e1af518b016de3aaff5d9$$aPfister, Stefan$$b32$$udkfz
000136677 7001_ $$0P:(DE-He78)a1f4b408b9155beb2a8f7cba4d04fe88$$aSahm, Felix$$b33$$udkfz
000136677 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b34$$eLast author$$udkfz
000136677 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-018-1865-4$$gVol. 136, no. 2, p. 239 - 253$$n2$$p239 - 253$$tActa neuropathologica$$v136$$x1432-0533$$y2018
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