Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy.
Methylation subgroup and molecular heterogeneity is a hallmark of glioblastoma: implications for biopsy targeting, classification and therapy.
复制标题
DOI：
10.1016/j.esmoop.2022.100566
复制
发表时间：
2022-10
期刊：
影响因子：
7.3
通讯作者：
Wiestler, B.
中科院分区：
文献类型：
--
作者：
Gempt, J.;Withake, F.;Aftahy, A. K.;Meyer, H. S.;Barz, M.;Delbridge, C.;Liesche-Starnecker, F.;Prokop, G.;Pfarr, N.;Schlegel, J.;Meyer, B.;Zimmer, C.;Menze, B. H.;Wiestler, B.
细胞和分子水平的肿瘤内异质性是胶质母细胞瘤（GB）的标志，导致治疗抵抗和不良临床结局。关于表观遗传异质性和瘤内遗传异质性及其对分子分类和靶向治疗的意义知之甚少。从来自前瞻性内部队列和公开可用数据的56名新诊断的未经治疗的GB患者中采集多个组织活检（总共238个），并使用Illumina MethylationEPIC阵列进行DNA甲基化分析。使用Ceccarelli等人开发的胶质瘤分类器进行基于甲基化的分类。并通过MGMT-STP 27模型估计MGMT启动子甲基化状态。此外，还分析了拷贝数变异（CNV）和重复性。几乎一半的患者（22/56，39%）携带由异质性甲基化亚型组成的肿瘤。我们发现了两种主要的亚型组合：经典/间充质样和间充质/毛细胞型星形细胞瘤样。9例患者（16%）的肿瘤由MGMT启动子甲基化和未甲基化的亚体积组成，而20例患者（36%）为均匀甲基化，27例患者（48%）为均匀非甲基化。CNV分析揭示了许多基因的高度变异，包括CDKN 2A/B、EGFR和PTEN。系统发育分析相应地显示了在肿瘤发展的早期阶段CDKN 2A/B丧失和EGFR、PDGFRA和CDK 4获得的一般模式。在DNA甲基化和CNV水平上，肿瘤内（Epi）遗传异质性是GB的标志。这种肿瘤内异质性对于分子分类以及确定这种疾病的治疗靶点至关重要，因为单次活检可能低估肿瘤中真正的分子多样性。胶质母细胞瘤表现出显著的异质性，从表观基因组范围的甲基化表型到单个分子靶点。系统发育显示CDKN 2A/B在肿瘤发展早期丢失和获得EGFR、PDGFRA和CDK 4。肿瘤内异质性对于分子分类以及确定治疗靶点至关重要。评估单个活检低估了肿瘤的真实分子多样性。
Intratumoral heterogeneity at the cellular and molecular level is a hallmark of glioblastoma (GB) that contributes to treatment resistance and poor clinical outcome. Little is known regarding epigenetic heterogeneity and intratumoral phylogeny and their implication for molecular classification and targeted therapies. Multiple tissue biopsies (238 in total) were sampled from 56 newly-diagnosed, treatment-naive GB patients from a prospective in-house cohort and publicly available data and profiled for DNA methylation using the Illumina MethylationEPIC array. Methylation-based classification using the glioma classifier developed by Ceccarelli et al. and estimation of the MGMT promoter methylation status via the MGMT-STP27 model were carried out. In addition, copy number variations (CNVs) and phylogeny were analyzed. Almost half of the patients (22/56, 39%) harbored tumors composed of heterogeneous methylation subtypes. We found two predominant subtype combinations: classic-/mesenchymal-like, and mesenchymal-/pilocytic astrocytoma-like. Nine patients (16%) had tumors composed of subvolumes with and without MGMT promoter methylation, whereas 20 patients (36%) were homogeneously methylated, and 27 patients (48%) were homogeneously unmethylated. CNV analysis revealed high variations in many genes, including CDKN2A/B, EGFR, and PTEN. Phylogenetic analysis correspondingly showed a general pattern of CDKN2A/B loss and gain of EGFR, PDGFRA, and CDK4 during early stages of tumor development. (Epi)genetic intratumoral heterogeneity is a hallmark of GB, both at DNA methylation and CNV level. This intratumoral heterogeneity is of utmost importance for molecular classification as well as for defining therapeutic targets in this disease, as single biopsies might underestimate the true molecular diversity in a tumor. Glioblastoma exhibits significant heterogeneity, from epigenome-wide methylation phenotypes to single molecular targets. Phylogeny showed CDKN2A/B loss and gain of EGFR, PDGFRA, and CDK4 early in tumor development. Intratumoral heterogeneity is of utmost importance for molecular classification as well as for defining therapeutic targets. Assessing single biopsies underestimates the true molecular diversity in a tumor.
登录
查看更多内容
影响因子：
48
作者：
Huber W;Carey VJ;Gentleman R;Anders S;Carlson M;Carvalho BS;Bravo HC;Davis S;Gatto L;Girke T;Gottardo R;Hahne F;Hansen KD;Irizarry RA;Lawrence M;Love MI;MacDonald J;Obenchain V;Oleś AK;Pagès H;Reyes A;Shannon P;Smyth GK;Tenenbaum D;Waldron L;Morgan M
通讯作者：
Morgan M
影响因子：
4.6
作者：
Parker NR;Hudson AL;Khong P;Parkinson JF;Dwight T;Ikin RJ;Zhu Y;Cheng ZJ;Vafaee F;Chen J;Wheeler HR;Howell VM
通讯作者：
Howell VM
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：
3.8
作者：
Dedeurwaerder, Sarah;Defrance, Matthieu;Fuks, Francois
通讯作者：
Fuks, Francois
影响因子：
16.6
作者：
Huang Y;Sun X;Jiang H;Yu S;Robins C;Armstrong MJ;Li R;Mei Z;Shi X;Gerasimov ES;De Jager PL;Bennett DA;Wingo AP;Jin P;Wingo TS;Qin ZS
通讯作者：
Qin ZS