Zhang Yu-An, Zhou Yunyun, Luo Xin, Song Kai, Ma Xiaotu, Sathe Adwait, Girard Luc, Xiao Guanghua, Gazdar Adi F
The Hamon Center for Therapeutic Oncology Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, MS 39216, USA.
EBioMedicine. 2016 Nov;13:80-89. doi: 10.1016/j.ebiom.2016.10.040. Epub 2016 Oct 28.
BACKGROUND: Diffuse gliomas, grades II and III, hereafter called lower-grade gliomas (LGG), have variable, difficult to predict clinical courses, resulting in multiple studies to identify prognostic biomarkers. The purpose of this study was to assess expression or methylation of the homeobox family gene SHOX2 as independent markers for LGG survival. METHODS: We downloaded publically available glioma datasets for gene expression and methylation. The Cancer Genome Atlas (TCGA) (LGG, n=516) was used as a training set, and three other expression datasets (n=308) and three other methylation datasets (n=320), were used for validation. We performed Kaplan-Meier survival curves and univariate and multivariate Cox regression model analyses. FINDINGS: SHOX2 expression and gene body methylation varied among LGG patients and highly significantly predicted poor overall survival. While they were tightly correlated, SHOX2 expression appeared more potent as a prognostic marker and was used for most further studies. The SHOX2 prognostic roles were maintained after analyses by histology subtypes or tumor grade. We found that the combination of SHOX2 expression and IDH genotype status identified a subset of LGG patients with IDH wild-type (IDHwt) and low SHOX2 expression with considerably favorable survival. We further investigated the combination of SHOX2 with other known clinically relevant markers of LGG (TERT expression, 1p/19q chromosome co-deletion, MGMT methylation, ATRX mutation and NES expression). When combined with SHOX2 expression, we identified subsets of LGG patients with significantly favorable survival outcomes, especially in the subgroup with worse prognosis for each individual marker. Finally, multivariate analysis demonstrated that SHOX2 was a potent independent survival marker. INTERPRETATION: We have identified that SHOX2 expression or methylation are potent independent prognostic indicators for predicting LGG patient survival, and have potential to identify an important subset of LGG patients with IDHwt status with significantly better overall survival. The combination of IDH or other relevant markers with SHOX2 identified LGG subsets with significantly different survival outcomes, and further understanding of these subsets may benefit therapeutic target identification and therapy selections for glioma patients.
背景：弥漫性二级和三级胶质瘤，以下称为低级别胶质瘤（LGG），其临床病程多变且难以预测，因此开展了多项研究以确定预后生物标志物。本研究的目的是评估同源盒家族基因SHOX2的表达或甲基化作为LGG生存的独立标志物。 方法：我们下载了公开可用的胶质瘤基因表达和甲基化数据集。癌症基因组图谱（TCGA）（LGG，n = 516）用作训练集，另外三个表达数据集（n = 308）和另外三个甲基化数据集（n = 320）用于验证。我们进行了Kaplan-Meier生存曲线分析以及单变量和多变量Cox回归模型分析。 研究结果：SHOX2表达和基因体甲基化在LGG患者中各不相同，并且高度显著地预测了较差的总生存期。虽然它们紧密相关，但SHOX2表达作为预后标志物似乎更有效，并用于大多数后续研究。在按组织学亚型或肿瘤分级分析后，SHOX2的预后作用依然存在。我们发现，SHOX2表达与异柠檬酸脱氢酶（IDH）基因型状态的组合确定了一部分IDH野生型（IDHwt）且SHOX2表达低的LGG患者，其生存期相当良好。我们进一步研究了SHOX2与其他已知的LGG临床相关标志物（TERT表达、1p/19q染色体共缺失、O6-甲基鸟嘌呤-DNA甲基转移酶（MGMT）甲基化、α地中海贫血/智力低下综合征X连锁基因（ATRX）突变和NES表达）的组合。当与SHOX2表达结合时，我们确定了生存期明显良好的LGG患者亚组，特别是在每个个体标志物预后较差的亚组中。最后，多变量分析表明SHOX2是一个有效的独立生存标志物。 解读：我们已经确定，SHOX2表达或甲基化是预测LGG患者生存的有效独立预后指标，并且有可能确定IDHwt状态的LGG患者的一个重要亚组，其总生存期明显更好。IDH或其他相关标志物与SHOX2的组合确定了生存期明显不同的LGG亚组，进一步了解这些亚组可能有助于胶质瘤患者的治疗靶点识别和治疗选择。
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