55岁以下患者野生型胶质母细胞瘤中的超突变与错配修复缺陷、微卫星不稳定性和巨细胞富集相关。

Ultra-Mutation in Wild-Type Glioblastomas of Patients Younger than 55 Years is Associated with Defective Mismatch Repair, Microsatellite Instability, and Giant Cell Enrichment.

作者信息

Barresi Valeria, Simbolo Michele, Mafficini Andrea, Piredda Maria Liliana, Caffo Maria, Cardali Salvatore Massimiliano, Germanò Antonino, Cingarlini Sara, Ghimenton Claudio, Scarpa Aldo

机构信息

Department of Diagnostics and Public Health, Section of Anatomical Pathology, University and Hospital Trust of Verona, 37134 Verona, Italy.

ARC-Net Research Centre, University and Hospital Trust of Verona, 37134 Verona, Italy.

出版信息

Cancers (Basel). 2019 Aug 30;11(9):1279. doi: 10.3390/cancers11091279.

BACKGROUND

Glioblastomas (GBMs) are classified into isocitrate dehydrogenase () mutants and IDH wild-types (-wt). This study aimed at identifying the mutational assets of -wt GBMs in patients aged 18-54 years for which limited data are available.

METHODS

Sixteen -wt GBMs from adults < 55 years old were explored for mutations, copy number variations, tumour mutational load (TML), and mutational spectrum by a 409 genes TML panel.

RESULTS

Eight (50%) -wt GBMs were hypermutated (TML > 9 mutations/Mb) and two (12.5%) were ultra-mutated (TML > 100 mutations/Mb). One ultra-mutated GBM had microsatellite instability (MSI), a somatic MSH6 mutation, and a germline POLE mutation. The other ultra-mutated GBMs had MSI and two somatic mutations in MSH2. Both ultra-mutated GBMs featured at least 25% giant cells. The overall survival of eight patients with hypermutated GBMs was significantly longer than that of patients with non-hypermutated GBMs ( = 0.04).

CONCLUSIONS

We identified a hyper-mutated subgroup among IDH-wt GBMs in adults < 55 years that had improved prognosis. Two cases were ultra-mutated and characterized by the presence of at least 25% giant cells, MMR mutations, and MSI. Since high TML has been associated with response to immune checkpoint inhibition in paediatric gliomas, the identification of a subtype of ultra-mutated IDH-wt GBM may have implications for immunotherapy.

背景

胶质母细胞瘤（GBM）分为异柠檬酸脱氢酶（IDH）突变型和IDH野生型（IDH-wt）。本研究旨在确定18 - 54岁患者中IDH-wt GBM的突变特征，目前这方面的数据有限。

方法

通过一个包含409个基因的肿瘤突变负荷（TML）检测板，对16例年龄小于55岁的成人IDH-wt GBM进行突变、拷贝数变异、肿瘤突变负荷（TML）和突变谱分析。

结果

8例（50%）IDH-wt GBM为高突变（TML > 9个突变/Mb），2例（12.5%）为超突变（TML > 100个突变/Mb）。1例超突变GBM具有微卫星不稳定性（MSI）、体细胞MSH6突变和种系POLE突变。另1例超突变GBM具有MSI和MSH2的两个体细胞突变。两例超突变GBM均有至少25%的巨细胞。高突变GBM的8例患者的总生存期显著长于非高突变GBM患者（P = 0.04）。