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000130418 1001_ $$aRivera, Barbara$$b0
000130418 245__ $$aGermline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors.
000130418 260__ $$aBerlin$$bSpringer$$c2016
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000130418 520__ $$aDysembryoplastic neuroepithelial tumor (DNET) is a benign brain tumor associated with intractable drug-resistant epilepsy. In order to identify underlying genetic alterations and molecular mechanisms, we examined three family members affected by multinodular DNETs as well as 100 sporadic tumors from 96 patients, which had been referred to us as DNETs. We performed whole-exome sequencing on 46 tumors and targeted sequencing for hotspot FGFR1 mutations and BRAF p.V600E was used on the remaining samples. FISH, copy number variation assays and Sanger sequencing were used to validate the findings. By whole-exome sequencing of the familial cases, we identified a novel germline FGFR1 mutation, p.R661P. Somatic activating FGFR1 mutations (p.N546K or p.K656E) were observed in the tumor samples and further evidence for functional relevance was obtained by in silico modeling. The FGFR1 p.K656E mutation was confirmed to be in cis with the germline p.R661P variant. In 43 sporadic cases, in which the diagnosis of DNET could be confirmed on central blinded neuropathology review, FGFR1 alterations were also frequent and mainly comprised intragenic tyrosine kinase FGFR1 duplication and multiple mutants in cis (25/43; 58.1 %) while BRAF p.V600E alterations were absent (0/43). In contrast, in 53 cases, in which the diagnosis of DNET was not confirmed, FGFR1 alterations were less common (10/53; 19 %; p < 0.0001) and hotspot BRAF p.V600E (12/53; 22.6 %) (p < 0.001) prevailed. We observed overexpression of phospho-ERK in FGFR1 p.R661P and p.N546K mutant expressing HEK293 cells as well as FGFR1 mutated tumor samples, supporting enhanced MAP kinase pathway activation under these conditions. In conclusion, constitutional and somatic FGFR1 alterations and MAP kinase pathway activation are key events in the pathogenesis of DNET. These findings point the way towards existing targeted therapies.
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000130418 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aFGFR1 protein, human
000130418 650_7 $$0EC 2.7.10.1$$2NLM Chemicals$$aReceptor, Fibroblast Growth Factor, Type 1
000130418 650_7 $$0EC 2.7.11.1$$2NLM Chemicals$$aProto-Oncogene Proteins B-raf
000130418 7001_ $$aGayden, Tenzin$$b1
000130418 7001_ $$aCarrot-Zhang, Jian$$b2
000130418 7001_ $$aNadaf, Javad$$b3
000130418 7001_ $$aBoshari, Talia$$b4
000130418 7001_ $$aFaury, Damien$$b5
000130418 7001_ $$aZeinieh, Michele$$b6
000130418 7001_ $$aBlanc, Romeo$$b7
000130418 7001_ $$aBurk, David L$$b8
000130418 7001_ $$aFahiminiya, Somayyeh$$b9
000130418 7001_ $$aBareke, Eric$$b10
000130418 7001_ $$aSchüller, Ulrich$$b11
000130418 7001_ $$aMonoranu, Camelia M$$b12
000130418 7001_ $$aSträter, Ronald$$b13
000130418 7001_ $$aKerl, Kornelius$$b14
000130418 7001_ $$aNiederstadt, Thomas$$b15
000130418 7001_ $$aKurlemann, Gerhard$$b16
000130418 7001_ $$aEllezam, Benjamin$$b17
000130418 7001_ $$aMichalak, Zuzanna$$b18
000130418 7001_ $$aThom, Maria$$b19
000130418 7001_ $$aLockhart, Paul J$$b20
000130418 7001_ $$aLeventer, Richard J$$b21
000130418 7001_ $$aOhm, Milou$$b22
000130418 7001_ $$aMacGregor, Duncan$$b23
000130418 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b24$$udkfz
000130418 7001_ $$aKaramchandani, Jason$$b25
000130418 7001_ $$aGreenwood, Celia M T$$b26
000130418 7001_ $$aBerghuis, Albert M$$b27
000130418 7001_ $$aBens, Susanne$$b28
000130418 7001_ $$aSiebert, Reiner$$b29
000130418 7001_ $$aZakrzewska, Magdalena$$b30
000130418 7001_ $$aLiberski, Pawel P$$b31
000130418 7001_ $$aZakrzewski, Krzysztof$$b32
000130418 7001_ $$aSisodiya, Sanjay M$$b33
000130418 7001_ $$aPaulus, Werner$$b34
000130418 7001_ $$aAlbrecht, Steffen$$b35
000130418 7001_ $$aHasselblatt, Martin$$b36
000130418 7001_ $$aJabado, Nada$$b37
000130418 7001_ $$aFoulkes, William D$$b38
000130418 7001_ $$aMajewski, Jacek$$b39
000130418 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-016-1549-x$$gVol. 131, no. 6, p. 847 - 863$$n6$$p847 - 863$$tActa neuropathologica$$v131$$x1432-0533$$y2016
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