The role of RB1 alteration and 4q12 amplification in IDH-WT glioblastoma.
The role of RB1 alteration and 4q12 amplification in IDH-WT glioblastoma.
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Rb1基因改变和4Q12扩增在IDH-WT胶质母细胞瘤中的作用
DOI：
10.1093/noajnl/vdab050
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发表时间：
2021-01
期刊：
影响因子：
--
通讯作者：
Esquenazi Y
中科院分区：
文献类型：
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作者：
Dono A;Ramesh AV;Wang E;Shah M;Tandon N;Ballester LY;Esquenazi Y
最近的研究发现，胶质母细胞瘤idh -野生型（GBM IDH-WT）可能由具有不同预后的分子亚群组成。因此，我们研究了282例GBM IDH-WT患者的遗传改变与生存之间的相关性，以确定具有不同结果的亚组。我们通过下一代测序分析205个基因和26个重排，回顾了2009-2019年GBM IDH-WT患者的特征。采用log-rank检验和Cox回归模型评估无进展生存期（PFS）和总生存期（OS）。我们利用来自cbiopportal （MSK-IMPACT数据集）的数据验证了我们的结果。对GBM IDH-WT的多变量分析显示，放化疗和rb1突变状态与改善PFS（风险比[HR] 0.25, P < .001和HR 0.47, P = .002）和OS（风险比[HR] 0.24, P < .001和HR 0.49, P = .016）相关。此外，年龄较小（<55岁）与OS改善相关。Karnofsky性能状态小于80 （HR 1.44, P = 0.024）和KDR扩增（HR 2.51, P = 0.008）是较差OS的预测因子。kdr扩增患者同时存在PDGFRA和KIT扩增（P < .001）和TP53突变（P = .04）。rb1突变患者CDKN2A/B和EGFR改变发生率较低（P < 0.001）。相反，rb1突变患者TP53 （P < 0.001）和SETD2 （P = 0.006）突变更频繁。MSK-IMPACT数据集的分析（n = 551）验证了RB1突变与改善的PFS （11.0 vs 8.7个月，P = 0.009）和OS （34.7 vs 21.7个月，P = 0.016）之间的关联。rb1突变体GBM IDH-WT是PFS和OS改善的分子亚群。同时，4q12扩增（KDR/PDGFRA/KIT）表示OS较差的患者。确定具有不同生存率的GBM IDH-WT亚组对于优化临床试验设计，结合靶向治疗和个性化神经肿瘤护理非常重要。
Recent studies have identified that glioblastoma IDH-wildtype (GBM IDH-WT) might be comprised of molecular subgroups with distinct prognoses. Therefore, we investigated the correlation between genetic alterations and survival in 282 GBM IDH-WT patients, to identify subgroups with distinct outcomes. We reviewed characteristics of GBM IDH-WT (2009–2019) patients analyzed by next-generation sequencing interrogating 205 genes and 26 rearrangements. Progression-free survival (PFS) and overall survival (OS) were evaluated with the log-rank test and Cox regression models. We validated our results utilizing data from cBioPortal (MSK-IMPACT dataset). Multivariable analysis of GBM IDH-WT revealed that treatment with chemoradiation and RB1-mutant status correlated with improved PFS (hazard ratio [HR] 0.25, P < .001 and HR 0.47, P = .002) and OS (HR 0.24, P < .001 and HR 0.49, P = .016). In addition, younger age (<55 years) was associated with improved OS. Karnofsky performance status less than 80 (HR 1.44, P = .024) and KDR amplification (HR 2.51, P = .008) were predictors of worse OS. KDR-amplified patients harbored coexisting PDGFRA and KIT amplification (P < .001) and TP53 mutations (P = .04). RB1-mutant patients had less frequent CDKN2A/B and EGFR alterations (P < .001). Conversely, RB1-mutant patients had more frequent TP53 (P < .001) and SETD2 (P = .006) mutations. Analysis of the MSK-IMPACT dataset (n = 551) validated the association between RB1 mutations and improved PFS (11.0 vs 8.7 months, P = .009) and OS (34.7 vs 21.7 months, P = .016). RB1-mutant GBM IDH-WT is a molecular subgroup with improved PFS and OS. Meanwhile, 4q12 amplification (KDR/PDGFRA/KIT) denoted patients with worse OS. Identifying subgroups of GBM IDH-WT with distinct survival is important for optimal clinical trial design, incorporation of targeted therapies, and personalized neuro-oncological care.