The EGFRvIII transcriptome in glioblastoma: A meta-omics analysis.
The EGFRvIII transcriptome in glioblastoma: A meta-omics analysis.
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DOI：
10.1093/neuonc/noab231
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发表时间：
2022-03-12
期刊：
影响因子：
15.9
通讯作者：
French PJ
中科院分区：
文献类型：
--
作者：
Hoogstrate Y;Ghisai SA;de Wit M;de Heer I;Draaisma K;van Riet J;van de Werken HJG;Bours V;Buter J;Vanden Bempt I;Eoli M;Franceschi E;Frenel JS;Gorlia T;Hanse MC;Hoeben A;Kerkhof M;Kros JM;Leenstra S;Lombardi G;Lukacova S;Robe PA;Sepulveda JM;Taal W;Taphoorn M;Vernhout RM;Walenkamp AME;Watts C;Weller M;de Vos FYF;Jenster GW;van den Bent M;French PJ
EGFR是胶质母细胞瘤中最常改变的基因之一，外显子2-7缺失（EGFRvIII）是其最常见的基因组突变之一。关于其预后作用的报道相互矛盾，目前仍不清楚与野生型EGFR相比，它在信号传导方面是否以及如何不同。为了更好地理解EGFRvIII的致癌作用，我们将4个大型数据集整合到1个大型胶质母细胞瘤转录组数据集（n = 741）中，以及来自2个数据集的81个全基因组样本。EGFRvIII/EGFR表达比率在肿瘤之间差异很大，范围为1%至95%。有趣的是，相对EGFRvIII表达的斜率是近线性的，这反对比EGFR野生型更积极的选择压力。EGFRvIII阳性和阴性胶质母细胞瘤患者的生存率相似也表明没有选择压力。EGFRvIII水平与pan-EGFR（所有野生型和突变变体）表达呈负相关，这表明EGFRvIII在下游途径激活中具有更高的效力。EGFRvIII阳性胶质母细胞瘤的CDK 4或MDM 2扩增发生率低于EGFRvIII阴性（P = 0.007），这可能表明这些途径之间存在串扰。与仅EGFR扩增的肿瘤相比，表达EGFRvIII的肿瘤具有“经典”亚型基因的上调（P = 3.873e−6）。EGFRvIII缺失的基因组断裂点倾向于大内含子-1的3′端。这些优选的断裂点保留了导致新的EGFRvIII变体的隐蔽外显子，并保留了内含子增强子。这些数据为复杂的EGFRvIII生物学提供了更深入的见解，并为靶向EGFRvIII突变肿瘤提供了新的见解。
EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being among its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signaling compared with wildtype EGFR. To better understand the oncogenic role of EGFRvIII, we leveraged 4 large datasets into 1 large glioblastoma transcriptome dataset (n = 741) alongside 81 whole-genome samples from 2 datasets. The EGFRvIII/EGFR expression ratios differ strongly between tumors and range from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII-positive and -negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (P = .007), which may point toward crosstalk between these pathways. EGFRvIII-expressing tumors have an upregulation of “classical” subtype genes compared to those with EGFR-amplification only (P = 3.873e−6). Genomic breakpoints of the EGFRvIII deletions have a preference toward the 3′-end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer. These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumors.
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影响因子：
28.2
作者：
Francis JM;Zhang CZ;Maire CL;Jung J;Manzo VE;Adalsteinsson VA;Homer H;Haidar S;Blumenstiel B;Pedamallu CS;Ligon AH;Love JC;Meyerson M;Ligon KL
通讯作者：
Ligon KL
影响因子：
64.5
作者：
Morton, Andrew R.;Dogan-Artun, Nergiz;Scacheri, Peter C.
通讯作者：
Scacheri, Peter C.
影响因子：
8.4
作者：
Erdem-Eraslan, Lale;Gao, Ya;French, Pim J.
通讯作者：
French, Pim J.
DOI：
10.1073/pnas.0912094107
发表时间：
2010-03-09
影响因子：
11.1
作者：
Fu, Xiaoyong;Yucer, Nur;Wang, Yi
通讯作者：
Wang, Yi
影响因子：
64.8
作者：
Chin, L.;Meyerson, M.;Aldape, K.;Bigner, D.;Mikkelsen, T.;VandenBerg, S.;Kahn, A.;Penny, R.;Ferguson, M. L.;Gerhard, D. S.;Getz, G.;Brennan, C.;Taylor, B. S.;Winckler, W.;Park, P.;Ladanyi, M.;Hoadley, K. A.;Verhaak, R. G. W.;Hayes, D. N.;Spellman, Paul T.;Absher, D.;Weir, B. A.;Ding, L.;Wheeler, D.;Lawrence, M. S.;Cibulskis, K.;Mardis, E.;Zhang, Jinghui;Wilson, R. K.;Donehower, L.;Wheeler, D. A.;Purdom, E.;Wallis, J.;Laird, P. W.;Herman, J. G.;Schuebel, K. E.;Weisenberger, D. J.;Baylin, S. B.;Schultz, N.;Yao, Jun;Wiedemeyer, R.;Weinstein, J.;Sander, C.;Gibbs, R. A.;Gray, J.;Kucherlapati, R.;Lander, E. S.;Myers, R. M.;Perou, C. M.;McLendon, Roger;Friedman, Allan;Van Meir, Erwin G;Brat, Daniel J;Mastrogianakis, Gena Marie;Olson, Jeffrey J;Lehman, Norman;Yung, W. K. Alfred;Bogler, Oliver;Berger, Mitchel;Prados, Michael;Muzny, Donna;Morgan, Margaret;Scherer, Steve;Sabo, Aniko;Nazareth, Lynn;Lewis, Lora;Hall, Otis;Zhu, Yiming;Ren, Yanru;Alvi, Omar;Yao, Jiqiang;Hawes, Alicia;Jhangiani, Shalini;Fowler, Gerald;San Lucas, Anthony;Kovar, Christie;Cree, Andrew;Dinh, Huyen;Santibanez, Jireh;Joshi, Vandita;Gonzalez-Garay, Manuel L.;Miller, Christopher A.;Milosavljevic, Aleksandar;Sougnez, Carrie;Fennell, Tim;Mahan, Scott;Wilkinson, Jane;Ziaugra, Liuda;Onofrio, Robert;Bloom, Toby;Nicol, Rob;Ardlie, Kristin;Baldwin, Jennifer;Gabriel, Stacey;Fulton, Robert S.;McLellan, Michael D.;Larson, David E.;Shi, Xiaoqi;Abbott, Rachel;Fulton, Lucinda;Chen, Ken;Koboldt, Daniel C.;Wendl, Michael C.;Meyer, Rick;Tang, Yuzhu;Lin, Ling;Osborne, John R.;Dunford-Shore, Brian H.;Miner, Tracie L.;Delehaunty, Kim;Markovic, Chris;Swift, Gary;Courtney, William;Pohl, Craig;Abbott, Scott;Hawkins, Amy;Leong, Shin;Haipek, Carrie;Schmidt, Heather;Wiechert, Maddy;Vickery, Tammi;Scott, Sacha;Dooling, David J.;Chinwalla, Asif;Weinstock, George M.;O'Kelly, Michael;Robinson, Jim;Alexe, Gabriele;Beroukhim, Rameen;Carter, Scott;Chiang, Derek;Gould, Josh;Gupta, Supriya;Korn, Josh;Mermel, Craig;Mesirov, Jill;Monti, Stefano;Nguyen, Huy;Parkin, Melissa;Reich, Michael;Stransky, Nicolas;Garraway, Levi;Golub, Todd;Protopopov, Alexei;Perna, Ilana;Aronson, Sandy;Sathiamoorthy, Narayan;Ren, Georgia;Kim, Hyunsoo;Kong, Sek Won;Xiao, Yonghong;Kohane, Isaac S.;Seidman, Jon;Cope, Leslie;Pan, Fei;Van Den Berg, David;Van Neste, Leander;Yi, Joo Mi;Li, Jun Z.;Southwick, Audrey;Brady, Shannon;Aggarwal, Amita;Chung, Tisha;Sherlock, Gavin;Brooks, James D.;Jakkula, Lakshmi R.;Lapuk, Anna V.;Marr, Henry;Dorton, Shannon;Choi, Yoon Gi;Han, Ju;Ray, Amrita;Wang, Victoria;Durinck, Steffen;Robinson, Mark;Wang, Nicholas J.;Vranizan, Karen;Peng, Vivian;Van Name, Eric;Fontenay, Gerald V.;Ngai, John;Conboy, John G.;Parvin, Bahram;Feiler, Heidi S.;Speed, Terence P.;Socci, Nicholas D.;Olshen, Adam;Lash, Alex;Reva, Boris;Antipin, Yevgeniy;Stukalov, Alexey;Gross, Benjamin;Cerami, Ethan;Wang, Wei Qing;Qin, Li-Xuan;Seshan, Venkatraman E.;Villafania, Liliana;Cavatore, Magali;Borsu, Laetitia;Viale, Agnes;Gerald, William;Topal, Michael D.;Qi, Yuan;Balu, Sai;Shi, Yan;Wu, George;Bittner, Michael;Shelton, Troy;Lenkiewicz, Elizabeth;Morris, Scott;Beasley, Debbie;Sanders, Sheri;Sfeir, Robert;Chen, Jessica;Nassau, David;Feng, Larry;Hickey, Erin;Schaefer, Carl;Madhavan, Subha;Buetow, Ken;Barker, Anna;Vockley, Joseph;Compton, Carolyn;Vaught, Jim;Fielding, Peter;Collins, Francis;Good, Peter;Guyer, Mark;Ozenberger, Brad;Peterson, Jane;Thomson, Elizabeth
通讯作者：
Thomson, Elizabeth