Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations.
Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations.
复制标题
与IDH 1-R132 H突变相比，非IDH 1-R132 H IDH 1/2突变与星形细胞瘤中DNA甲基化增加和生存率提高相关。
DOI：
10.1007/s00401-021-02291-6
复制
发表时间：
2021-06
影响因子：
12.7
通讯作者：
French PJ
中科院分区：
文献类型：
--
作者：
Tesileanu CMS;Vallentgoed WR;Sanson M;Taal W;Clement PM;Wick W;Brandes AA;Baurain JF;Chinot OL;Wheeler H;Gill S;Griffin M;Rogers L;Rudà R;Weller M;McBain C;Reijneveld J;Enting RH;Caparrotti F;Lesimple T;Clenton S;Gijtenbeek A;Lim E;de Vos F;Mulholland PJ;Taphoorn MJB;de Heer I;Hoogstrate Y;de Wit M;Boggiani L;Venneker S;Oosting J;Bovée JVMG;Erridge S;Vogelbaum MA;Nowak AK;Mason WP;Kros JM;Wesseling P;Aldape K;Jenkins RB;Dubbink HJ;Baumert B;Golfinopoulos V;Gorlia T;van den Bent M;French PJ
异柠檬酸脱氢酶基因IDH 1和IDH 2的体细胞突变在几种肿瘤类型中发生频率很高。尽管这些突变仅限于不同的热点，但我们发现神经胶质瘤是唯一一种IDH 1 R132 H突变百分比异常高的肿瘤类型。与具有其他IDH 1/2突变（“非R132 H IDH 1/2突变”）的肿瘤相比，具有IDH 1 R132 H突变肿瘤的患者具有较低水平的全基因组DNA甲基化和相关的基因表达增加。这种甲基化降低在多种肿瘤类型中均可见，因此似乎与起源部位无关。对于1 p/19 q非共缺失胶质瘤（星形细胞瘤）患者，我们发现这种差异具有临床意义：在随机III期CATNON试验的样本中，携带IDH突变而不是IDH 1 R132 H的肿瘤患者具有更好的结局（风险比0.41，95% CI [0.24，0.71]，p = 0.0013）。这种非R132 H IDH 1/2突变的肿瘤也具有显著较低比例的肿瘤，其被分配到遗传学上差的DNA甲基化类别（p < 0.001）。IDH突变类型在包含已知临床和分子预后因素的多变量模型中是独立的。为了证实这些观察结果，我们验证了IDH突变类型对大型独立数据集的预后影响。观察到非R132 H IDH 1/2突变的星形细胞瘤比其IDH 1 R132 H突变的对应物具有更有利的预后，表明并非所有IDH突变都是相同的。这一差异具有临床相关性，在患者诊断时应予以考虑。在线版本包含补充材料，可通过10.1007/s 00401 -021-02291-6获得。
Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H IDH1/2 mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication. The online version contains supplementary material available at 10.1007/s00401-021-02291-6.
登录
查看更多内容
影响因子：
64.8
作者：
Capper D;Jones DTW;Sill M;Hovestadt V;Schrimpf D;Sturm D;Koelsche C;Sahm F;Chavez L;Reuss DE;Kratz A;Wefers AK;Huang K;Pajtler KW;Schweizer L;Stichel D;Olar A;Engel NW;Lindenberg K;Harter PN;Braczynski AK;Plate KH;Dohmen H;Garvalov BK;Coras R;Hölsken A;Hewer E;Bewerunge-Hudler M;Schick M;Fischer R;Beschorner R;Schittenhelm J;Staszewski O;Wani K;Varlet P;Pages M;Temming P;Lohmann D;Selt F;Witt H;Milde T;Witt O;Aronica E;Giangaspero F;Rushing E;Scheurlen W;Geisenberger C;Rodriguez FJ;Becker A;Preusser M;Haberler C;Bjerkvig R;Cryan J;Farrell M;Deckert M;Hench J;Frank S;Serrano J;Kannan K;Tsirigos A;Brück W;Hofer S;Brehmer S;Seiz-Rosenhagen M;Hänggi D;Hans V;Rozsnoki S;Hansford JR;Kohlhof P;Kristensen BW;Lechner M;Lopes B;Mawrin C;Ketter R;Kulozik A;Khatib Z;Heppner F;Koch A;Jouvet A;Keohane C;Mühleisen H;Mueller W;Pohl U;Prinz M;Benner A;Zapatka M;Gottardo NG;Driever PH;Kramm CM;Müller HL;Rutkowski S;von Hoff K;Frühwald MC;Gnekow A;Fleischhack G;Tippelt S;Calaminus G;Monoranu CM;Perry A;Jones C;Jacques TS;Radlwimmer B;Gessi M;Pietsch T;Schramm J;Schackert G;Westphal M;Reifenberger G;Wesseling P;Weller M;Collins VP;Blümcke I;Bendszus M;Debus J;Huang A;Jabado N;Northcott PA;Paulus W;Gajjar A;Robinson GW;Taylor MD;Jaunmuktane Z;Ryzhova M;Platten M;Unterberg A;Wick W;Karajannis MA;Mittelbronn M;Acker T;Hartmann C;Aldape K;Schüller U;Buslei R;Lichter P;Kool M;Herold-Mende C;Ellison DW;Hasselblatt M;Snuderl M;Brandner S;Korshunov A;von Deimling A;Pfister SM
通讯作者：
Pfister SM
影响因子：
3.7
作者：
Jin G;Reitman ZJ;Spasojevic I;Batinic-Haberle I;Yang J;Schmidt-Kittler O;Bigner DD;Yan H
通讯作者：
Yan H
DOI：
10.1016/s1470-2045(20)30157-1
发表时间：
2020-06
期刊：
The Lancet. Oncology
影响因子：
--
作者：
Abou-Alfa GK;Macarulla T;Javle MM;Kelley RK;Lubner SJ;Adeva J;Cleary JM;Catenacci DV;Borad MJ;Bridgewater J;Harris WP;Murphy AG;Oh DY;Whisenant J;Lowery MA;Goyal L;Shroff RT;El-Khoueiry AB;Fan B;Wu B;Chamberlain CX;Jiang L;Gliser C;Pandya SS;Valle JW;Zhu AX
通讯作者：
Zhu AX
影响因子：
158.5
作者：
DiNardo, C. D.;Stein, E. M.;Kantarjian, H. M.
通讯作者：
Kantarjian, H. M.
影响因子：
64.5
作者：
Ceccarelli M;Barthel FP;Malta TM;Sabedot TS;Salama SR;Murray BA;Morozova O;Newton Y;Radenbaugh A;Pagnotta SM;Anjum S;Wang J;Manyam G;Zoppoli P;Ling S;Rao AA;Grifford M;Cherniack AD;Zhang H;Poisson L;Carlotti CG Jr;Tirapelli DP;Rao A;Mikkelsen T;Lau CC;Yung WK;Rabadan R;Huse J;Brat DJ;Lehman NL;Barnholtz-Sloan JS;Zheng S;Hess K;Rao G;Meyerson M;Beroukhim R;Cooper L;Akbani R;Wrensch M;Haussler D;Aldape KD;Laird PW;Gutmann DH;TCGA Research Network;Noushmehr H;Iavarone A;Verhaak RG
通讯作者：
Verhaak RG