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

  • Laboratory Investigation
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

Results

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).

Conclusions

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.

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Acknowledgements

This study was supported by Shenghua Yuying Project of Central South University to L.Y., National Science Foundation of China to XJL (81472594 and 81770781), and National Science and Technology Major Project to B.X. (2016YFC0904400).

Author information

Authors and Affiliations

  1. Department of Neurology, The Second Xiangya Hospital, Central South University, No. 139 Middle Renmin Road, Changsha, 410011, Hunan, People’s Republic of China

    Lei Tang, Lu Deng & Li Yang

  2. Department of Radiology, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Harrison X. Bai & James Sun

  3. Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, 410078, Hunan, People’s Republic of China

    Ya Cao & Yongguang Tao

  4. Department of Neurology, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Jing Wu & Bo Xiao

  5. Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, 10050, People’s Republic of China

    Yinyan Wang

  6. Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Boston, MA, 02129, USA

    Ken Chang

  7. Department of Radiology, Brigham and Women’s Hospital, Boston, MA, 02115, USA

    Raymond Y. Huang

  8. Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Paul J. Zhang

  9. Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, 410008, Hunan, People’s Republic of China

    Xuejun Li

  10. Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, 19104, USA

    Natalie Neale

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  1. Lei Tang
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Electronic supplementary material

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11060_2018_2915_MOESM1_ESM.tif

Supplementary Figure 1. The expression of 5 DNA repair genes on chromosome arms 1q and 19p in patients with versus without 1p19q codeletion. (TIF 128 KB)

11060_2018_2915_MOESM2_ESM.tif

Supplementary Figure 2. The expression of 5 most upregulated and 5 most downregulated non-DNA repair genes on chromosome arms 1p and 19q relative to non-glioma sample in patients with versus without 1p19q codeletion. (TIF 1377 KB)

11060_2018_2915_MOESM3_ESM.tif

Supplementary Figure 3. Progression free survival of patients who received chemotherapy between low expression and high expression for (A) LIG1, (B) POLD1, (C) PNKP, (D) RAD54L, (E) MUTYH. (TIF 1463 KB)

11060_2018_2915_MOESM4_ESM.tif

Supplementary Figure 4. Overall survival of patients who received chemotherapy between low expression and high expression for (A) LIG1, (B) POLD1, (C) PNKP, (D) RAD54L, (E) MUTYH. (TIF 1488 KB)

11060_2018_2915_MOESM5_ESM.tif

Supplementary Figure 5. Results of RT-qPCR of HS683 cell line demonstrate good knockdown efficiency for shRAD54L#1, shRAD54L#2, shRAD54L#3, shMUTYH#1, shMUTYH#2, shMUTYH#3, shLIG1#1, shLIG1#2, shLIG1#3, shPNKP#1, shPNKP#2, shPNKP#3, shPOLD1#1 and shPOLD1#2. (TIF 276 KB)

11060_2018_2915_MOESM6_ESM.tif

Supplementary Figure 6. Results of RT-qPCR of U251 cell line demonstrate good knockdown efficiency for shRAD54L#1, shRAD54L#2, shRAD54L#3, shMUTYH#1, shMUTYH#2, shMUTYH#3, shLIG1#1, shLIG1#2, shLIG1#3, shPNKP#1, shPNKP#2, shPNKP#3, shPOLD1#1 and shPOLD1#2. (TIF 265 KB)

11060_2018_2915_MOESM7_ESM.tif

Supplementary Figure 7. MTS curve after knockdown sequence of GFP for: (A) HS683-2mg/L TMZ, (B) U251-2mg/L TMZ, (C) HS683-5mg/L TMZ, (D) U251-5mg/L TMZ, (E) HS683-10mg/L TMZ, (F) U251-10mg/L TMZ. (TIF 201 KB)

11060_2018_2915_MOESM8_ESM.tif

Supplementary Figure 8. MTS curve of HS683 cell line at 5mg/L for: (A) RAD54L, (B) MUTYH, (C) LIG1, (D) PNKP, (E) POLD1. *, p&#x003C;0.05; **, p&#x003C;0.01; ***, p&#x003C;0.001. (TIF 221 KB)

11060_2018_2915_MOESM9_ESM.tif

Supplementary Figure 9. MTS curve of U251 cell line at 5mg/L for: (A) RAD54L, (B) MUTYH, (C) LIG1, (D) PNKP, (E) POLD1. *, p&#x003C;0.05; **, p&#x003C;0.01; ***, p&#x003C;0.001. (TIF 215 KB)

11060_2018_2915_MOESM10_ESM.tif

Supplementary Figure 10. MTS curve of HS683 cell line at 10mg/L for: (A) RAD54L, (B) MUTYH, (C) LIG1, (D) PNKP, (E) POLD1. *, p&#x003C;0.05; **, p&#x003C;0.01; ***, p&#x003C;0.001. (TIF 220 KB)

11060_2018_2915_MOESM11_ESM.tif

Supplementary Figure 11. MTS curve of U251 cell line at 10mg/L for: (A) RAD54L, (B) MUTYH, (C) LIG1, (D) PNKP, (E) POLD1. *, p&#x003C;0.05; **, p&#x003C;0.01; ***, p&#x003C;0.001. (TIF 216 KB)

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Tang, L., Deng, L., Bai, H.X. et al. Reduced expression of DNA repair genes and chemosensitivity in 1p19q codeleted lower-grade gliomas. J Neurooncol 139, 563–571 (2018). https://doi.org/10.1007/s11060-018-2915-4

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