DataSheet1_Gene signatures associated with prognosis and chemotherapy resistance in glioblastoma treated with temozolomide.DOCX

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）的预后仍极差。为发掘胶质母细胞瘤全新的药物靶点与生物标志物，本研究针对接受替莫唑胺治疗的胶质母细胞瘤患者，筛选出与患者生存及替莫唑胺耐药相关的基因特征。
方法：本研究纳入癌症基因组图谱（The Cancer Genome Atlas）中接受替莫唑胺治疗的221例胶质母细胞瘤病例，通过基于网络的分层聚类方法，将体细胞突变（somatic mutations）影响基因互作网络（gene interaction network）中相似功能模块的患者按中位总生存期（median overall survival, mOS）划分为不同亚组。选取中位总生存期最长的亚组中的差异突变基因构建基因特征，并在独立数据集中验证其与患者生存及替莫唑胺耐药的关联。此外，在37例独立胶质母细胞瘤病例队列中，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，其中第4亚组（71例受试者）的中位总生存期最长，为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分别构建了20基因和8基因特征模型，可在两个独立数据集中预测患者总生存期（实际总生存期与预测总生存期的斯皮尔曼相关系数（Spearman’s rho）分别为0.64和0.58；p<0.001）。在37例胶质母细胞瘤的小型独立队列中，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个所构建的特征模型，可在三个独立数据集中将替莫唑胺耐药的胶质母细胞瘤样本与对照样本区分（曲线下面积（area under the curve）≥0.75）。预后特征与替莫唑胺耐药特征共有8个重合基因：ANG、BACH1、CDKN2C、HMGA1、IFI16、PADI4、SDF4及TP53INP1，其中后3个基因此前未被报道与胶质母细胞瘤相关。
结论：PADI4、SDF4及TP53INP1可作为胶质母细胞瘤全新的治疗靶点与生物标志物候选分子。对这些基因的肿瘤生物学功能开展进一步研究，或可为阐明胶质母细胞瘤的治疗耐药机制提供新视角。