Department of Neurology, The Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, People's Republic of China.
Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104, USA.
J Neurooncol. 2018 Sep;139(3):563-571. doi: 10.1007/s11060-018-2915-4. Epub 2018 Jun 19.
Lower-grade gliomas (LGGs, defined as WHO grades II and III) with 1p19q codeletion have increased chemosensitivity when compared to LGGs without 1p19q codeletion, but the mechanism is currently unknown.
RNAseq data from 515 LGG patients in the Cancer Genome Atlas (TCGA) were analyzed to compare the effect of expression of the 9 DNA repair genes located on chromosome arms 1p and 19q on progression free survival (PFS) and overall survival (OS) between patients who received chemotherapy and those who did not. Chemosensitivity of cells with DNA repair genes knocked down was tested using MTS cell proliferation assay in HS683 cell line and U251 cell line.
The expression of 9 DNA repair genes on 1p and 19q was significantly lower in 1p19q-codeleted tumors (n = 175) than in tumors without the codeletion (n = 337) (p < 0.001). In LGG patients who received chemotherapy, lower expression of LIG1, POLD1, PNKP, RAD54L and MUTYH was associated with longer PFS and OS. This difference between chemotherapy and non-chemotherapy groups in the association of gene expression with survival was not observed in non-DNA repair genes located on chromosome arms 1p and 19q. MTS assays showed that knockdown of DNA repair genes LIG1, POLD1, PNKP, RAD54L and MUTYH significantly inhibited recovery in response to temozolomide when compared with control group (p < 0.001).
Our results suggest that reduced expression of DNA repair genes on chromosome arms 1p and 19q may account for the increased chemosensitivity of LGGs with 1p19q codeletion.
与未发生 1p19q 缺失的低级别神经胶质瘤（LGG，定义为世界卫生组织[WHO]分级 II 和 III）相比，发生 1p19q 缺失的 LGG 对化疗药物更敏感，但目前其机制尚不清楚。
分析 515 例来自癌症基因组图谱（TCGA）的 LGG 患者的 RNAseq 数据，比较发生 1p19q 缺失和未发生 1p19q 缺失的 LGG 患者中，位于 1p 和 19q 染色体臂上的 9 个 DNA 修复基因的表达对无进展生存期（PFS）和总生存期（OS）的影响。通过 MTS 细胞增殖试验，在 HS683 细胞系和 U251 细胞系中检测 DNA 修复基因敲低的细胞的化疗敏感性。
与未发生缺失的肿瘤（n=337）相比，发生 1p19q 缺失的肿瘤（n=175）中 9 个 DNA 修复基因在 1p 和 19q 上的表达明显降低（p<0.001）。在接受化疗的 LGG 患者中，LIG1、POLD1、PNKP、RAD54L 和 MUTYH 的表达水平较低与较长的 PFS 和 OS 相关。在未发生 DNA 修复基因位于 1p 和 19q 染色体臂上的 LGG 患者中，化疗组和非化疗组的基因表达与生存之间的这种关联差异并不明显。MTS 试验表明，与对照组相比，LIG1、POLD1、PNKP、RAD54L 和 MUTYH 的 DNA 修复基因敲低显著抑制了对替莫唑胺的反应恢复（p<0.001）。
我们的结果表明，染色体臂 1p 和 19q 上的 DNA 修复基因表达降低可能是发生 1p19q 缺失的 LGG 对化疗药物更敏感的原因。
