Table10_Gene signatures associated with prognosis and chemotherapy resistance in glioblastoma treated with temozolomide.XLSX

Background: Glioblastoma (GBM) prognosis remains extremely poor despite standard treatment that includes temozolomide (TMZ) chemotherapy. To discover new GBM drug targets and biomarkers, genes signatures associated with survival and TMZ resistance in GBM patients treated with TMZ were identified.
Methods: GBM cases in The Cancer Genome Atlas who received TMZ (n = 221) were stratified into subgroups that differed by median overall survival (mOS) using network-based stratification to cluster patients whose somatic mutations affected genes in similar modules of a gene interaction network. Gene signatures formed from differentially mutated genes in the subgroup with the longest mOS were used to confirm their association with survival and TMZ resistance in independent datasets. Somatic mutations in these genes also were assessed for an association with OS in an independent group of 37 GBM cases.
Results: Among the four subgroups identified, subgroup four (n = 71 subjects) exhibited the longest mOS at 18.3 months (95% confidence interval: 16.2, 34.1; p = 0.0324). Subsets of the 86 genes that were differentially mutated in this subgroup formed 20-gene and 8-gene signatures that predicted OS in two independent datasets (Spearman’s rho of 0.64 and 0.58 between actual and predicted OS; p < 0.001). Patients with mutations in five of the 86 genes had longer OS in a small, independent sample of 37 GBM cases, but this association did not reach statistical significance (p = 0.07). Thirty-one of the 86 genes formed signatures that distinguished TMZ-resistant GBM samples from controls in three independent datasets (area under the curve ≥ 0.75). The prognostic and TMZ-resistance signatures had eight genes in common (ANG, BACH1, CDKN2C, HMGA1, IFI16, PADI4, SDF4, and TP53INP1). The latter three genes have not been associated with GBM previously.
Conclusion:PADI4, SDF4, and TP53INP1 are novel therapy and biomarker candidates for GBM. Further investigation of their oncologic functions may provide new insight into GBM treatment resistance mechanisms.

背景：尽管采用包括替莫唑胺（temozolomide, TMZ）化疗在内的标准治疗方案，胶质母细胞瘤（Glioblastoma, GBM）患者的预后仍极差。为发掘新的GBM药物靶点与生物标志物，本研究对接受TMZ治疗的GBM患者中与生存及TMZ耐药相关的基因特征进行了鉴定。
方法：本研究纳入癌症基因组图谱（The Cancer Genome Atlas, TCGA）中接受TMZ治疗的GBM病例（n = 221），采用基于网络的分层（network-based stratification）方法，将体细胞突变（somatic mutations）影响基因互作网络（gene interaction network）相似模块的患者进行聚类，按中位总生存期（median overall survival, mOS）将病例分为不同亚组。从最长mOS亚组的差异突变基因（differentially mutated genes）中构建基因特征，并在独立数据集（independent datasets）中验证其与生存及TMZ耐药的关联。同时，在37例GBM患者组成的独立队列中，评估这些基因的体细胞突变与总生存期（overall survival, OS）的相关性。
结果：共鉴定出4个亚组，其中亚组4（n = 71例受试者）的中位总生存期最长，达18.3个月（95%置信区间：16.2~34.1；p = 0.0324）。该亚组中86个差异突变基因的子集可构建20基因及8基因特征，在两个独立数据集中可预测总生存期（实际与预测总生存期的斯皮尔曼秩相关系数（Spearman’s rho）分别为0.64和0.58；p < 0.001）。在37例GBM患者组成的小型独立队列中，携带86个基因中5个基因突变的患者总生存期更长，但该关联未达到统计学显著性（p = 0.07）。86个基因中的31个可构建特征，在三个独立数据集中可区分TMZ耐药GBM样本与对照样本（曲线下面积（area under the curve）≥ 0.75）。预后特征与TMZ耐药特征共包含8个重叠基因：ANG、BACH1、CDKN2C、HMGA1、IFI16、PADI4、SDF4及TP53INP1。其中后3个基因此前未被报道与GBM相关。
结论：PADI4、SDF4及TP53INP1可作为GBM新型治疗及生物标志物候选靶点。对其肿瘤生物学功能的进一步研究，可为GBM治疗耐药机制提供新的见解。