Reduced expression of DNA repair genes and chemosensitivity in 1p19q codeleted lower-grade gliomas

BackgroundLower-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.MethodsRNAseq 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.ResultsThe 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).ConclusionsOur 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.