Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation.
Stem cell phenotype predicts therapeutic response in glioblastomas with MGMT promoter methylation.
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DOI：
10.1186/s40478-022-01459-9
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发表时间：
2022-11-04
影响因子：
7.1
通讯作者：
中科院分区：
文献类型：
--
作者：
越来越多的证据支持胶质母细胞瘤（GBM）中存在具有干细胞样表型的细胞群，其与成体神经干细胞共享某些生物学标记，包括SOX 2、CD 133（PROM 1）和内斯（巢蛋白）的表达。本研究旨在确定这些干细胞标志物的表达与GBM患者临床结局之间的关系。我们通过免疫组织化学（IHC）定量了86例IDH-野生型GBM患者的蛋白质CD 133和SOX 2表达强度，并使用Kaplan-Meier和考克斯比例风险分析评估了患者结局。在我们的患者中，MGMT启动子甲基化状态和年龄是总生存期和无进展生存期的预测因子。在单变量分析中，SOX 2和CD 133的水平与结果无关;然而，基于CD 133或SOX 2表达的低或高水平的肿瘤分层显示，MGMT甲基化仅是CD 133或SOX 2表达水平高的肿瘤的无进展生存期和总生存期的预测因子。CD 133或SOX 2表达水平低的肿瘤没有显示出MGMT甲基化与生存之间的任何关系。MGMT和干细胞标志物之间的这种关系在第二个患者队列TCGA数据集中得到了证实。我们的研究结果表明，通过CD 133和SOX 2的表达水平对GBM进行分层，提高了MGMT启动子甲基化状态的预后能力，确定了一个低表达组，其中临床结局与MGMT启动子甲基化状态无关，以及一个高表达组，其中结局与MGMT启动子甲基化状态密切相关。这些发现支持GBM中高干细胞表型的存在（如通过SOX 2或CD 133的表达所标记的）可能与对治疗的临床应答相关的概念。 在线版本包含补充材料，可通过10.1186/s40478-022-01459-9获得。
A growing body of evidence supports the presence of a population of cells in glioblastoma (GBM) with a stem cell-like phenotype which shares certain biological markers with adult neural stem cells, including expression of SOX2, CD133 (PROM1), and NES (nestin). This study was designed to determine the relationship between the expression of these stem cell markers and the clinical outcome in GBM patients. We quantified the intensity of expression of the proteins CD133 and SOX2 by immunohistochemistry (IHC) in a cohort of 86 patients with IDH-wildtype GBM, and evaluated patient outcomes using Kaplan–Meier and Cox proportional hazards analysis. In our patients, MGMT promoter methylation status and age were predictors of overall survival and progression free survival. The levels of SOX2 and CD133 were not associated with outcome in univariate analysis; however, stratification of tumors based on low or high levels of CD133 or SOX2 expression revealed that MGMT methylation was a predictor of progression-free survival and overall survival only for tumors with high levels of expression of CD133 or SOX2. Tumors with low levels of expression of CD133 or SOX2 did not show any relationship between MGMT methylation and survival. This relationship between MGMT and stem cell markers was confirmed in a second patient cohort, the TCGA dataset. Our results show that stratification of GBM by the level of expression of CD133 and SOX2 improved the prognostic power of MGMT promoter methylation status, identifying a low-expressing group in which the clinical outcome is not associated with MGMT promoter methylation status, and a high-expressing group in which the outcome was strongly associated with MGMT promoter methylation status. These findings support the concept that the presence of a high stem cell phenotype in GBM, as marked by expression of SOX2 or CD133, may be associated with the clinical response to treatment. The online version contains supplementary material available at 10.1186/s40478-022-01459-9.
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影响因子：
7.4
作者：
Melguizo C;Prados J;González B;Ortiz R;Concha A;Alvarez PJ;Madeddu R;Perazzoli G;Oliver JA;López R;Rodríguez-Serrano F;Aránega A
通讯作者：
Aránega A
影响因子：
37.3
作者：
Beier D;Schulz JB;Beier CP
通讯作者：
Beier CP
DOI：
10.1002/aac2.12043
发表时间：
2021-12
期刊：
Aging and cancer
影响因子：
--
作者：
Audesse, Amanda J;Karashchuk, Galina;Gardell, Zachary A;Lakis, Nelli S;Maybury-Lewis, Sun Y;Brown, Abigail K;Leeman, Dena S;Teo, Yee Voan;Neretti, Nicola;Anthony, Douglas C;Brodsky, Alexander S;Webb, Ashley E
通讯作者：
Webb, Ashley E
影响因子：
64.5
作者：
Malta TM;Sokolov A;Gentles AJ;Burzykowski T;Poisson L;Weinstein JN;Kamińska B;Huelsken J;Omberg L;Gevaert O;Colaprico A;Czerwińska P;Mazurek S;Mishra L;Heyn H;Krasnitz A;Godwin AK;Lazar AJ;Cancer Genome Atlas Research Network;Stuart JM;Hoadley KA;Laird PW;Noushmehr H;Wiznerowicz M
通讯作者：
Wiznerowicz M
影响因子：
15.9
作者：
Ostrom, Quinn T.;Cioffi, Gino;Barnholtz-Sloan, Jill S.
通讯作者：
Barnholtz-Sloan, Jill S.