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IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations.
Brain Pathology ( IF 5.8 ) Pub Date : 2019-12-03 , DOI: 10.1111/bpa.12801
Rui Ryan Yang 1, 2 , Zhi-Feng Shi 3 , Zhen-Yu Zhang 4 , Aden Ka-Yin Chan 2 , Abudumijiti Aibaidula 3 , Wei-Wei Wang 5 , Johnny Sheung Him Kwan 2 , Wai Sang Poon 6 , Hong Chen 7 , Wen-Cai Li 5 , Nellie Yuk-Fei Chung 2 , Gopika Punchhi 2 , William Ching-Yuen Chu 2 , Ivan Sik-Hei Chan 2 , Xian-Zhi Liu 4 , Ying Mao 3 , Kay Ka-Wai Li 2 , Ho-Keung Ng 2
Affiliation  

In the 2016, WHO classification of tumors of the central nervous system, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower grade astrocytomas and IDH-mutated astrocytomas is now regarded as a single group with longer survival. However, the molecular and clinical heterogeneity among IDH mutant lower grade (WHO Grades II/III) astrocytomas have only rarely been investigated. In this study, we recruited 160 IDH mutant lower grade (WHO Grades II/III) astrocytomas, and examined PDGFRA amplification, CDKN2A deletion and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A homozygous deletion and CDK4 amplification in 18.8%, 15.0% and 18.1% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (P = 0.0003) and OS (P < 0.0001). In tumors without PDGFRA amplification, CDKN2A homozygous deletion or CDK4 amplification was associated with a shorter OS (P = 0.035). Tumors were divided into three risk groups based on the presence of molecular alterations: high risk (PDGFRA amplification), intermediate risk (CDKN2A deletion or CDK4 amplification) and low risk (neither CDKN2A deletion and CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.5, 62.9 and 71.5 months. The high-risk group also demonstrated a shorter PFS compared to intermediate- (P = 0.036) and low-risk (P < 0.0001) groups. One limitation of this study is the relatively short follow-up period, a common confounding factor for studies on low-grade tumors. Our data illustrate that IDH mutant lower grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.

中文翻译:

IDH 突变低级别(WHO II/III 级)星形细胞瘤可以通过 CDKN2A、CDK4 和 PDGFRA 拷贝数改变进行风险分层。

在 2016 年 WHO 中枢神经系统肿瘤分类中,异柠檬酸脱氢酶 (IDH) 突变是低级别星形细胞瘤的主要分类,而 IDH 突变的星形细胞瘤现在被视为具有更长生存期的单一组别。然而,很少研究 IDH 突变低级别(WHO II/III 级)星形细胞瘤之间的分子和临床异质性。在这项研究中,我们招募了 160 名 IDH 突变低级别(WHO II/III 级)星形细胞瘤,并通过 FISH 分析检查了 PDGFRA 扩增、CDKN2A 缺失和 CDK4 扩增,通过 Sanger 测序检查了 TERT 启动子突变,通过免疫组织化学检查了 ATRX 缺失和 p53 表达。我们分别在 18.8%、15.0% 和 18.1% 的队列中发现了 PDGFRA 扩增、CDKN2A 纯合缺失和 CDK4 扩增,而这些变化是以一种相互排斥的方式发生的。PDGFRA 扩增与较短的 PFS (P = 0.0003) 和 OS (P < 0.0001) 相关。在没有 PDGFRA 扩增的肿瘤中,CDKN2A 纯合缺失或 CDK4 扩增与较短的 OS 相关(P = 0.035)。根据分子改变的存在,将肿瘤分为三个风险组:高风险(PDGFRA 扩增)、中风险(CDKN2A 缺失或 CDK4 扩增)和低风险(既没有 CDKN2A 缺失,也没有 CDK4 扩增,也没有 PDGFRA 扩增)。这三个风险组的总生存期显着不同,平均生存期分别为 40.5、62.9 和 71.5 个月。与中等风险(P = 0.036)和低风险(P < 0.0001)组相比,高风险组也表现出更短的 PFS。这项研究的一个限制是相对较短的随访期,这是低级别肿瘤研究的常见混杂因素。我们的数据表明 IDH 突变的低级别星形细胞瘤不是一个同质的群体,应该对风险进行分子分层。
更新日期:2019-12-03
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