Ülgen Ege, Can Özge, Bilguvar Kaya, Oktay Yavuz, Akyerli Cemaliye B, Danyeli Ayça Erşen, Yakıcıer M Cengiz, Sezerman O Uğur, Pamir M Necmettin, Özduman Koray
Departments of1Biostatistics and Medical Informatics.
2Department of Medical Engineering, Acibadem Mehmet Ali Aydınlar University, School of Engineering, Istanbul, Turkey.
J Neurosurg. 2019 Apr 5;132(5):1435-1446. doi: 10.3171/2019.1.JNS182938. Print 2020 May 1.
Processes that cause or contribute to cancer, such as aging, exposure to carcinogens, or DNA damage repair deficiency (DDRd), create predictable and traceable nucleotide alterations in one's genetic code (termed "mutational signatures"). Large studies have previously identified various such mutational signatures across cancers that can be attributed to the specific causative processes. To gain further insight into the processes in glioma development, the authors analyzed mutational signatures in adult diffuse gliomas (DGs).
Twenty-five DGs and paired blood samples were whole exome sequenced. Somatic mutational signatures were identified using 2 different methods. Associations of the signatures with age at diagnosis, molecular subset, and mutational load were investigated. As DDRd-related signatures were frequently observed, germline and somatic DDR gene mutations as well as microsatellite instability (MSI) status were determined for all samples. For validation of signature prevalence, publicly available data from The Cancer Genome Atlas (TCGA) were used.
Each tumor had a unique combination of signatures. The most common signatures were signature 1 (88%, aging related), signature 3 (52%, homologous recombination related), and signature 15 (56%, mismatch repair related). Eighty-four percent of the tumors contained at least 1 DDRd signature. The findings were validated using public TCGA data. The weight of signature 1 positively correlated with age (r = 0.43) while cumulative weight of DDRd signatures negatively correlated with age (r = -0.16). Each subject had at least 1 germline/somatic alteration in a DDR gene, the most common being the risk single nucleotide polymorphism rs1800734 in MLH1. The rs1800734-AA genotype had a higher cumulative DDRd weight as well as higher mutational load; TP53 was the most common somatically altered DDR gene. MSI was observed in 24% of the tumors. No significant associations of MSI status with mutational load, rs1800734, or the cumulative weight of DDRd signatures were identified.
Current findings suggest that DDRd may act as a fundamental mechanism in gliomagenesis rather than being a random, secondary event.
导致或促成癌症的过程，如衰老、接触致癌物或DNA损伤修复缺陷（DDRd），会在一个人的遗传密码中产生可预测和可追踪的核苷酸改变（称为“突变特征”）。此前的大型研究已在各种癌症中识别出多种此类可归因于特定致病过程的突变特征。为了更深入了解胶质瘤发生发展的过程，作者分析了成人弥漫性胶质瘤（DG）中的突变特征。
对25例DG及其配对的血液样本进行全外显子组测序。使用两种不同方法识别体细胞突变特征。研究这些特征与诊断时年龄、分子亚组和突变负荷的关联。由于经常观察到与DDRd相关的特征，因此确定了所有样本的种系和体细胞DDR基因突变以及微卫星不稳定性（MSI）状态。为验证特征的普遍性，使用了来自癌症基因组图谱（TCGA）的公开数据。
每个肿瘤都有独特的特征组合。最常见的特征是特征1（88%，与衰老相关）、特征3（52%，与同源重组相关）和特征15（56%）。84%的肿瘤至少含有1个DDRd特征。研究结果通过TCGA公开数据得到验证。特征1的权重与年龄呈正相关（r = 0.43），而DDRd特征的累积权重与年龄呈负相关（r = -0.16）。每个受试者的DDR基因至少有1种种系/体细胞改变，最常见的是MLH1中具有风险的单核苷酸多态性rs1800734。rs1800734-AA基因型具有更高的DDRd累积权重以及更高的突变负荷；TP53是最常见的体细胞改变的DDR基因。24%的肿瘤中观察到MSI。未发现MSI状态与突变负荷、rs1800734或DDRd特征的累积权重之间存在显著关联。
目前的研究结果表明，DDRd可能是胶质瘤发生的一种基本机制，而非随机的次要事件。
