IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations
IDH mutant lower grade (WHO Grades II/III) astrocytomas can be stratified for risk by CDKN2A, CDK4 and PDGFRA copy number alterations
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IDH 突变低级（WHO II/III 级）星形细胞瘤可通过 CDKN2A、CDK4 和 PDGFRA 拷贝数改变进行风险分层
DOI：
10.1111/bpa.12801
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发表时间：
2019-12-03
期刊：
影响因子：
6.4
通讯作者：
Ng, Ho-Keung
中科院分区：
文献类型：
--
作者：
Yang, Rui Ryan;Shi, Zhi-feng;Ng, Ho-Keung
在2016年，WHO对中枢神经系统肿瘤的分类中，异柠檬酸脱氢酶（IDH）突变是低级别星形细胞瘤的主要分类器，IDH突变的星形细胞瘤现在被认为是生存期较长的单一组。然而，IDH突变型低级别（WHO II/III级）星形细胞瘤的分子和临床异质性很少被研究。在这项研究中，我们招募了160例IDH突变型低级别（WHO分级II/III）星形细胞瘤，并通过FISH分析检测PDGFRA扩增、CDKN 2A缺失和CDK 4扩增，通过桑格测序检测TERT启动子突变，通过免疫组化检测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、CDKN 2A纯合缺失和CDK 4扩增，并且这些改变以相互排斥的方式发生。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，CDKN 2A纯合缺失或CDK 4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），中等风险（CDKN 2A缺失或CDK 4扩增）和低风险（既没有CDKN 2A缺失和CDK 4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。高风险组的PFS也短于中风险组（P = 0.036）和低风险组（P < 0.0001）。这项研究的一个局限性是随访时间相对较短，这是低级别肿瘤研究的一个常见混杂因素。我们的数据表明IDH突变型低级别星形细胞瘤不是一个同质组，应该根据风险进行分子分层。
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.