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000136782 0247_ $$2doi$$a10.1007/s00401-018-1877-0
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000136782 1001_ $$0P:(DE-He78)a7c1bbac024fa232d9c6b78443328d9d$$aPajtler, Kristian$$b0$$eFirst author
000136782 245__ $$aMolecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas.
000136782 260__ $$aBerlin$$bSpringer$$c2018
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000136782 520__ $$aOf nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors.
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000136782 7001_ $$aWen, Ji$$b1
000136782 7001_ $$0P:(DE-He78)45440b44791309bd4b7dbb4f73333f9b$$aSill, Martin$$b2$$eFirst author
000136782 7001_ $$aLin, Tong$$b3
000136782 7001_ $$aOrisme, Wilda$$b4
000136782 7001_ $$aTang, Bo$$b5
000136782 7001_ $$0P:(DE-He78)a8c698e0904394407c5261932915daa5$$aHübner, Jens-Martin$$b6
000136782 7001_ $$aRamaswamy, Vijay$$b7
000136782 7001_ $$aJia, Sujuan$$b8
000136782 7001_ $$aDalton, James D$$b9
000136782 7001_ $$aHaupfear, Kelly$$b10
000136782 7001_ $$aRogers, Hazel A$$b11
000136782 7001_ $$aPunchihewa, Chandanamali$$b12
000136782 7001_ $$aLee, Ryan$$b13
000136782 7001_ $$aEaston, John$$b14
000136782 7001_ $$aWu, Gang$$b15
000136782 7001_ $$aRitzmann, Timothy A$$b16
000136782 7001_ $$aChapman, Rebecca$$b17
000136782 7001_ $$0P:(DE-He78)082dd3179733e3e716a58eb90f418a78$$aChavez, Lukas$$b18
000136782 7001_ $$aBoop, Fredrick A$$b19
000136782 7001_ $$aKlimo, Paul$$b20
000136782 7001_ $$aSabin, Noah D$$b21
000136782 7001_ $$aOgg, Robert$$b22
000136782 7001_ $$aMack, Stephen C$$b23
000136782 7001_ $$aFreibaum, Brian D$$b24
000136782 7001_ $$aKim, Hong Joo$$b25
000136782 7001_ $$0P:(DE-He78)046fd145f1008f83f6236580727bbc0f$$aWitt, Hendrik$$b26
000136782 7001_ $$0P:(DE-He78)551bb92841f634070997aa168d818492$$aJones, David$$b27
000136782 7001_ $$aVo, Baohan$$b28
000136782 7001_ $$aGajjar, Amar$$b29
000136782 7001_ $$aPounds, Stan$$b30
000136782 7001_ $$aOnar-Thomas, Arzu$$b31
000136782 7001_ $$aRoussel, Martine F$$b32
000136782 7001_ $$aZhang, Jinghui$$b33
000136782 7001_ $$aTaylor, J Paul$$b34
000136782 7001_ $$aMerchant, Thomas E$$b35
000136782 7001_ $$aGrundy, Richard$$b36
000136782 7001_ $$aTatevossian, Ruth G$$b37
000136782 7001_ $$aTaylor, Michael D$$b38
000136782 7001_ $$0P:(DE-HGF)0$$aPfister, Stefan M$$b39
000136782 7001_ $$0P:(DE-He78)8d9c904a6cea14d4c99c78ba46e41f93$$aKorshunov, Andrey$$b40
000136782 7001_ $$0P:(DE-He78)4c28e2aade5f44d8eca9dd8e97638ec8$$aKool, Marcel$$b41$$eLast author
000136782 7001_ $$aEllison, David W$$b42
000136782 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-018-1877-0$$gVol. 136, no. 2, p. 211 - 226$$n2$$p211 - 226$$tActa neuropathologica$$v136$$x1432-0533$$y2018
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