Abstract：
OBJECTIVE: Glioblastoma (GBM) is the most common malignant primary brain tumor with a dismal prognosis of less than 2 years under maximal therapy. Despite the poor prognosis, small fractions of GBM patients seem to have a markedly longer survival than the vast majority of patients. Recently discovered intertumoral heterogeneity is thought to be responsible for this peculiarity, although the exact underlying mechanisms remain largely unknown. Here, we investigated the epigenetic contribution to survival.
METHODS: GBM treatment-naïve samples from 53 patients, consisting of 12 extremely long-term survivors (eLTS) patients and 41 median-term survivors (MTS) patients, were collected for DNA methylation analysis. 865 859 CpG sites were examined and processed for detection of differentially methylated CpG positions (DMP) and regions (DMR) between both survival groups. Gene Ontology (GO) and pathway functional annotations were used to identify associated biological processes. Verification of these findings was done using The Cancer Genome Atlas (TCGA) database.
RESULTS: We identified 67 DMPs and 5 DMRs that were associated with genes and pathways - namely reduced interferon beta signaling, in MAPK signaling and in NTRK signaling - which play a role in survival in GBM.
CONCLUSIONS: In conclusion, baseline DNA methylation differences already present in treatment-naïve GBM samples are part of genes and pathways that play a role in the survival of these tumor types and therefore may explain part of the intrinsic heterogeneity that determines prognosis in GBM patients.
METHODS: GBM treatment-naïve samples from 53 patients, consisting of 12 extremely long-term survivors (eLTS) patients and 41 median-term survivors (MTS) patients, were collected for DNA methylation analysis. 865 859 CpG sites were examined and processed for detection of differentially methylated CpG positions (DMP) and regions (DMR) between both survival groups. Gene Ontology (GO) and pathway functional annotations were used to identify associated biological processes. Verification of these findings was done using The Cancer Genome Atlas (TCGA) database.
RESULTS: We identified 67 DMPs and 5 DMRs that were associated with genes and pathways - namely reduced interferon beta signaling, in MAPK signaling and in NTRK signaling - which play a role in survival in GBM.
CONCLUSIONS: In conclusion, baseline DNA methylation differences already present in treatment-naïve GBM samples are part of genes and pathways that play a role in the survival of these tumor types and therefore may explain part of the intrinsic heterogeneity that determines prognosis in GBM patients.
摘要：
目的：胶质母细胞瘤（GBM）是最常见的恶性原发性脑肿瘤，在最大限度的治疗下，预后差不到2年。尽管预后不佳,与绝大多数患者相比,小部分GBM患者的生存期明显更长.最近发现的肿瘤间异质性被认为是造成这种特殊性的原因。尽管确切的潜在机制仍在很大程度上未知。这里,我们调查了表观遗传对生存的贡献.
方法：来自53名患者的GBM治疗初治样本，由12名极端长期幸存者（ETS）患者和41名中期幸存者（MTS）患者组成，收集用于DNA甲基化分析。检查865859个CpG位点并对其进行处理,以检测两个存活组之间的差异甲基化CpG位置(DMP)和区域(DMR)。基因本体论(GO)和通路功能注释用于鉴定相关的生物过程。使用癌症基因组图谱(TCGA)数据库进行这些发现的验证。
结果：我们确定了67个DMPs和5个DMRs，它们与基因和通路相关，即干扰素β信号传导降低，MAPK信号和NTRK信号-在GBM的生存中起作用。
结论：结论：已经存在于未治疗GBM样本中的基线DNA甲基化差异是在这些肿瘤类型的存活中起作用的基因和通路的一部分,因此可以解释部分决定GBM患者预后的内在异质性。
方法：来自53名患者的GBM治疗初治样本，由12名极端长期幸存者（ETS）患者和41名中期幸存者（MTS）患者组成，收集用于DNA甲基化分析。检查865859个CpG位点并对其进行处理,以检测两个存活组之间的差异甲基化CpG位置(DMP)和区域(DMR)。基因本体论(GO)和通路功能注释用于鉴定相关的生物过程。使用癌症基因组图谱(TCGA)数据库进行这些发现的验证。
结果：我们确定了67个DMPs和5个DMRs，它们与基因和通路相关，即干扰素β信号传导降低，MAPK信号和NTRK信号-在GBM的生存中起作用。
结论：结论：已经存在于未治疗GBM样本中的基线DNA甲基化差异是在这些肿瘤类型的存活中起作用的基因和通路的一部分,因此可以解释部分决定GBM患者预后的内在异质性。
