全肿瘤分析揭示了 TERT 启动子突变的早期起源和 TERT 表达的细胞间异质性。
Whole tumor analysis reveals early origin of the TERT promoter mutation and intercellular heterogeneity in TERT expression.
机构信息
Department of Neurological Surgery, University of California, San Francisco, California, USA.
Department of Neuropathology, University of Heidelberg, Institute of Pathology, Heidelberg, Germany.
出版信息
Neuro Oncol. 2024 Apr 5;26(4):640-652. doi: 10.1093/neuonc/noad231.
BACKGROUND
The TERT promoter mutation (TPM) is acquired in most IDH-wildtype glioblastomas (GBM) and IDH-mutant oligodendrogliomas (OD) enabling tumor cell immortality. Previous studies on TPM clonality show conflicting results. This study was performed to determine whether TPM is clonal on a tumor-wide scale.
METHODS
We investigated TPM clonality in relation to presumed early events in 19 IDH-wildtype GBM and 10 IDH-mutant OD using 3-dimensional comprehensive tumor sampling. We performed Sanger sequencing on 264 tumor samples and deep amplicon sequencing on 187 tumor samples. We obtained tumor purity and copy number estimates from whole exome sequencing. TERT expression was assessed by RNA-seq and RNAscope.
RESULTS
We detected TPM in 100% of tumor samples with quantifiable tumor purity (219 samples). Variant allele frequencies (VAF) of TPM correlate positively with chromosome 10 loss in GBM (R = 0.85), IDH1 mutation in OD (R = 0.87), and with tumor purity (R = 0.91 for GBM; R = 0.90 for OD). In comparison, oncogene amplification was tumor-wide for MDM4- and most EGFR-amplified cases but heterogeneous for MYCN and PDGFRA, and strikingly high in low-purity samples. TPM VAF was moderately correlated with TERT expression (R = 0.52 for GBM; R = 0.65 for OD). TERT expression was detected in a subset of cells, solely in TPM-positive samples, including samples equivocal for tumor.
CONCLUSIONS
On a tumor-wide scale, TPM is among the earliest events in glioma evolution. Intercellular heterogeneity of TERT expression, however, suggests dynamic regulation during tumor growth. TERT expression may be a tumor cell-specific biomarker.
背景
TERT 启动子突变（TPM）在大多数 IDH 野生型胶质母细胞瘤（GBM）和 IDH 突变性少突胶质细胞瘤（OD）中获得，从而使肿瘤细胞获得永生。先前关于 TPM 克隆性的研究结果存在矛盾。本研究旨在确定 TPM 是否在肿瘤广泛范围内具有克隆性。
方法
我们使用三维全面肿瘤取样方法，研究了 19 例 IDH 野生型 GBM 和 10 例 IDH 突变性 OD 中 TPM 克隆性与假定的早期事件之间的关系。我们对 264 个肿瘤样本进行了 Sanger 测序，对 187 个肿瘤样本进行了深度扩增子测序。我们从全外显子测序中获得了肿瘤纯度和拷贝数估计值。通过 RNA-seq 和 RNAscope 评估 TERT 表达。
结果
我们在具有可量化肿瘤纯度的 100％的肿瘤样本中检测到了 TPM（219 个样本）。GBM 中 TPM 的变异等位基因频率（VAF）与 10 号染色体缺失呈正相关（R=0.85），OD 中 IDH1 突变呈正相关（R=0.87），与肿瘤纯度呈正相关（GBM 为 R=0.91；OD 为 R=0.90）。相比之下，MDM4 和大多数 EGFR 扩增的情况下，癌基因扩增是全肿瘤范围的，但 MYCN 和 PDGFRA 的扩增是异质性的，在低纯度样本中则非常高。TPM VAF 与 TERT 表达中度相关（GBM 为 R=0.52；OD 为 R=0.65）。在 TPM 阳性样本中，包括肿瘤不确定的样本，检测到 TERT 表达的细胞亚群。
结论
在肿瘤广泛范围内，TPM 是胶质瘤进化中的最早事件之一。然而，TERT 表达的细胞间异质性表明在肿瘤生长过程中存在动态调节。TERT 表达可能是肿瘤细胞特异性的生物标志物。
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