000127281 001__ 127281
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000127281 0247_ $$2doi$$a10.1038/nature14980
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000127281 0247_ $$2pmc$$apmc:PMC4881306
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000127281 0247_ $$2ISSN$$a1476-4687
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000127281 037__ $$aDKFZ-2017-03306
000127281 041__ $$aeng
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000127281 1001_ $$aPeifer, Martin$$b0
000127281 245__ $$aTelomerase activation by genomic rearrangements in high-risk neuroblastoma.
000127281 260__ $$aLondon [u.a.]$$bNature Publ. Group$$c2015
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000127281 520__ $$aNeuroblastoma is a malignant paediatric tumour of the sympathetic nervous system. Roughly half of these tumours regress spontaneously or are cured by limited therapy. By contrast, high-risk neuroblastomas have an unfavourable clinical course despite intensive multimodal treatment, and their molecular basis has remained largely elusive. Here we have performed whole-genome sequencing of 56 neuroblastomas (high-risk, n = 39; low-risk, n = 17) and discovered recurrent genomic rearrangements affecting a chromosomal region at 5p15.33 proximal of the telomerase reverse transcriptase gene (TERT). These rearrangements occurred only in high-risk neuroblastomas (12/39, 31%) in a mutually exclusive fashion with MYCN amplifications and ATRX mutations, which are known genetic events in this tumour type. In an extended case series (n = 217), TERT rearrangements defined a subgroup of high-risk tumours with particularly poor outcome. Despite a large structural diversity of these rearrangements, they all induced massive transcriptional upregulation of TERT. In the remaining high-risk tumours, TERT expression was also elevated in MYCN-amplified tumours, whereas alternative lengthening of telomeres was present in neuroblastomas without TERT or MYCN alterations, suggesting that telomere lengthening represents a central mechanism defining this subtype. The 5p15.33 rearrangements juxtapose the TERT coding sequence to strong enhancer elements, resulting in massive chromatin remodelling and DNA methylation of the affected region. Supporting a functional role of TERT, neuroblastoma cell lines bearing rearrangements or amplified MYCN exhibited both upregulated TERT expression and enzymatic telomerase activity. In summary, our findings show that remodelling of the genomic context abrogates transcriptional silencing of TERT in high-risk neuroblastoma and places telomerase activation in the centre of transformation in a large fraction of these tumours.
000127281 536__ $$0G:(DE-HGF)POF3-312$$a312 - Functional and structural genomics (POF3-312)$$cPOF3-312$$fPOF III$$x0
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000127281 650_7 $$2NLM Chemicals$$aChromatin
000127281 650_7 $$2NLM Chemicals$$aMYCN protein, human
000127281 650_7 $$2NLM Chemicals$$aN-Myc Proto-Oncogene Protein
000127281 650_7 $$2NLM Chemicals$$aNuclear Proteins
000127281 650_7 $$2NLM Chemicals$$aOncogene Proteins
000127281 650_7 $$2NLM Chemicals$$aRNA, Messenger
000127281 650_7 $$0EC 2.7.7.49$$2NLM Chemicals$$aTERT protein, human
000127281 650_7 $$0EC 2.7.7.49$$2NLM Chemicals$$aTelomerase
000127281 650_7 $$0EC 3.6.4.-$$2NLM Chemicals$$aDNA Helicases
000127281 650_7 $$0EC 3.6.4.12$$2NLM Chemicals$$aATRX protein, human
000127281 7001_ $$0P:(DE-HGF)0$$aHertwig, Falk$$b1
000127281 7001_ $$0P:(DE-HGF)0$$aRoels, Frederik$$b2
000127281 7001_ $$0P:(DE-He78)00d281bd33b8c1254cbe4f048dbfaa14$$aDreidax, Daniel$$b3$$udkfz
000127281 7001_ $$0P:(DE-He78)5190aa0a28a0d3d663954c463290e4c1$$aGartlgruber, Moritz$$b4$$udkfz
000127281 7001_ $$aMenon, Roopika$$b5
000127281 7001_ $$aKrämer, Andrea$$b6
000127281 7001_ $$aRoncaioli, Justin L$$b7
000127281 7001_ $$aSand, Frederik$$b8
000127281 7001_ $$aHeuckmann, Johannes M$$b9
000127281 7001_ $$aIkram, Fakhera$$b10
000127281 7001_ $$aSchmidt, Rene$$b11
000127281 7001_ $$aAckermann, Sandra$$b12
000127281 7001_ $$aEngesser, Anne$$b13
000127281 7001_ $$aKahlert, Yvonne$$b14
000127281 7001_ $$aVogel, Wenzel$$b15
000127281 7001_ $$aAltmüller, Janine$$b16
000127281 7001_ $$aNürnberg, Peter$$b17
000127281 7001_ $$aThierry-Mieg, Jean$$b18
000127281 7001_ $$aThierry-Mieg, Danielle$$b19
000127281 7001_ $$aMariappan, Aruljothi$$b20
000127281 7001_ $$aHeynck, Stefanie$$b21
000127281 7001_ $$aMariotti, Erika$$b22
000127281 7001_ $$0P:(DE-He78)a579ca2567736066534409e732b31c91$$aHenrich, Kai-Oliver$$b23$$udkfz
000127281 7001_ $$aGloeckner, Christian$$b24
000127281 7001_ $$aBosco, Graziella$$b25
000127281 7001_ $$aLeuschner, Ivo$$b26
000127281 7001_ $$aSchweiger, Michal R$$b27
000127281 7001_ $$0P:(DE-HGF)0$$aSavelyeva, Larissa$$b28
000127281 7001_ $$aWatkins, Simon C$$b29
000127281 7001_ $$aShao, Chunxuan$$b30
000127281 7001_ $$aBell, Emma$$b31
000127281 7001_ $$aHöfer, Thomas$$b32
000127281 7001_ $$aAchter, Viktor$$b33
000127281 7001_ $$aLang, Ulrich$$b34
000127281 7001_ $$aTheissen, Jessica$$b35
000127281 7001_ $$aVolland, Ruth$$b36
000127281 7001_ $$0P:(DE-He78)609d3f1c1420bf59b2332eeab889cb74$$aSaadati, Maral$$b37$$udkfz
000127281 7001_ $$aEggert, Angelika$$b38
000127281 7001_ $$ade Wilde, Bram$$b39
000127281 7001_ $$aBerthold, Frank$$b40
000127281 7001_ $$aPeng, Zhiyu$$b41
000127281 7001_ $$aZhao, Chen$$b42
000127281 7001_ $$aShi, Leming$$b43
000127281 7001_ $$aOrtmann, Monika$$b44
000127281 7001_ $$aBüttner, Reinhard$$b45
000127281 7001_ $$aPerner, Sven$$b46
000127281 7001_ $$aHero, Barbara$$b47
000127281 7001_ $$aSchramm, Alexander$$b48
000127281 7001_ $$0P:(DE-He78)91317a47fc8532e3daf0d0b362c2a27e$$aSchulte, Johannes$$b49$$udkfz
000127281 7001_ $$0P:(DE-He78)be4a5aeed7282c071b3ff43e9685c48c$$aHerrmann, Carl$$b50$$udkfz
000127281 7001_ $$aO'Sullivan, Roderick J$$b51
000127281 7001_ $$0P:(DE-He78)91f32735ee876c579d63c05a7f4778dd$$aWestermann, Frank$$b52$$eLast author$$udkfz
000127281 7001_ $$aThomas, Roman K$$b53
000127281 7001_ $$0P:(DE-HGF)0$$aFischer, Matthias$$b54$$eLast author
000127281 773__ $$0PERI:(DE-600)1413423-8$$a10.1038/nature14980$$gVol. 526, no. 7575, p. 700 - 704$$n7575$$p700 - 704$$tNature <London>$$v526$$x1476-4687$$y2015
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