Tumor Biology

, Volume 37, Issue 2, pp 1941–1947 | Cite as

G648C variant of DNA polymerase β sensitizes esophageal cancer to chemotherapy

  • Yuanyuan Wang
  • Qianqian Sun
  • Wei Guo
  • Xiaonan Chen
  • Yuwen Du
  • Wenqiao Zang
  • Ziming Dong
  • Guoqiang Zhao
Original Article


Human DNA polymerase β (polβ) is a small monomeric protein that is essential for short-patch base excision repair. It plays an important role in regulating the sensitivity of tumor cells to chemotherapy. We have previously identified a G to C point mutation at nucleotide 648 (G648C) of polβ in esophageal cancer (EC). In this study, we evaluated the mutation of polβ in a larger cohort of EC patients by RT-PCR and sequencing analysis. The function of the mutation was evaluated by MTT, in vivo tumor growth, and flow cytometry assays. The G648C mutation occurred in 15 (3.45 %) of 435 EC patients. In addition, patients with this mutation had significantly longer survival time than those without, following postoperative chemotherapy. Cell lines with G648C mutation in polβ gene were more sensitive to treatment with 5-fluorouracil and cisplatin than those with wild-type polβ. These results suggest that polβ gene with G648C mutation in surgically resected esophagus may be clinically useful for predicting responsiveness to chemotherapy in patients with EC. The polβ gene alteration may serve as a prognostic biomarker for EC.


Esophageal cancer DNA polymerase β Chemotherapy Point mutation 



This study was supported by National Natural Science Foundation of China (No. 81272188).

Conflicts of interest



  1. 1.
    Goodman MF. Error-prone repair DNA polymerases in prokaryotes and eukaryotes. Annu Rev Biochem. 2002;71:17–50.CrossRefPubMedGoogle Scholar
  2. 2.
    Nowak R, Woszczynski M, Siedlecki JA. Changes in the DNA polymerase beta gene expression during development of lung, brain, and testis suggest an involvement of the enzyme in DNA recombination. Exp Cell Res. 1990;191:51–6.CrossRefPubMedGoogle Scholar
  3. 3.
    Krahn JM, Beard WA, Wilson SH. Structural insights into DNA polymerase beta deterrents for misincorporation support an induced-fit mechanism for fidelity. Structure. 2004;12(10):1823–32.CrossRefPubMedGoogle Scholar
  4. 4.
    Prasad R, Batra VK, Yang XP, Krahn JM, Pedersen LC, Beard WA, et al. Structural insight into the DNA polymerase beta deoxyribose phosphate lyase mechanism. DNA Repair (Amst). 2005;4(12):1347–57.CrossRefGoogle Scholar
  5. 5.
    Friedberg EC. DNA damage and repair. Nature. 2003;421:436–40.CrossRefPubMedGoogle Scholar
  6. 6.
    Kidane D, Jonason AS, Gorton TS, Mihaylov I, Pan J, Keeney S, et al. DNA polymerase beta is critical for mouse meiotic synapsis. EMBO J. 2010;29:410–23.CrossRefPubMedGoogle Scholar
  7. 7.
    Wilson TE, Lieber MR. Efficient processing of DNA ends during yeast nonhomologous end joining. Evidence for a DNA polymerase b (Pol4)-dependent pathway. J Biol Chem. 1999;274:23599–609.CrossRefPubMedGoogle Scholar
  8. 8.
    Dalal S, Chikova A, Jaeger J, Sweasy JB. The Leu22Pro tumor-associated variant of DNA polymerase beta is dRP lyase deficient. Nucleic Acids Res. 2008;36:411–22.CrossRefPubMedGoogle Scholar
  9. 9.
    Canitrot Y, Hoffmann JS, Calsou P, Hayakawa H, Salles B, Cazaux C. Nucleotide excision repair DNA synthesis by excess DNA polymerase beta: a potential source of genetic instability in cancer cells. FASEB J. 2000;14:1765–74.CrossRefPubMedGoogle Scholar
  10. 10.
    Srivastava DK, Husain I, Arteaga CL, Wilson SH. DNA polymerase beta expression differences in selected human tumors and cell lines. Carcinogenesis. 1999;20:1049–54.CrossRefPubMedGoogle Scholar
  11. 11.
    Bhattacharyya N, Chen HC, Comhair S, Erzurum SC, Banerjee S. Variant forms of DNA polymerase beta in primary lung carcinomas. DNA Cell Biol. 1999;18:549–54.CrossRefPubMedGoogle Scholar
  12. 12.
    Dobashi Y, Shuin T, Tsuruga H, Uemura H, Torigoe S, Kubota Y. DNA polymerase beta gene mutation in human prostate cancer. Cancer Res. 1994;54:2827–39.PubMedGoogle Scholar
  13. 13.
    Miyamoto H, Miyagi Y, Ishikawa T, Ichikawa Y, Hosaka M, Kubota Y. DNA polymerase beta gene mutation in human breast cancer. Int J Cancer. 1999;83:708–19.CrossRefPubMedGoogle Scholar
  14. 14.
    Wang L, Patel U, Ghosh L, Banerjee S. DNA polymerase beta mutations in human colorectal cancer. Cancer Res. 1992;52:4824–7.PubMedGoogle Scholar
  15. 15.
    Zhao GQ, Wang T, Zhao Q, Yang HY, Tan XH, Dong ZM. Mutation of DNA polymerase beta in esophageal carcinoma of different regions. World J Gastroenterol. 2005;11:4618–22.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Feng L, Ma YY, Zhao GQ, Li M, Sun SJ, Dong ZM, et al. Establishment and characterization of DNA pol beta knockout human esophageal carcinoma cell line EC9706. Life Sci J. 2010;7:13–8.Google Scholar
  17. 17.
    Siegel R, Ma J, Zou Z, Jemal A. Cancer statistics, 2014. CA Cancer J Clin. 2014;64:9–29.CrossRefPubMedGoogle Scholar
  18. 18.
    Parkin DM, Pisani P, Ferlay J. Estimates of the worldwide incidence of 25 major cancers in 1990. Int J Cancer. 1999;80:827–41.CrossRefPubMedGoogle Scholar
  19. 19.
    Li M, Zang W, Wang Y, Ma Y, Xuan X, Zhao J, et al. DNA polymerase beta mutations and survival of patients with esophageal squamous cell carcinoma in Linzhou City, China. Tumour Biol. 2014;35:553–9.CrossRefPubMedGoogle Scholar
  20. 20.
    Li M, Zang W, Wang Y, Li Y, Ma Y, Wang N, et al. DNA polymerase beta promoter mutations and transcriptional activity in esophageal squamous cell carcinoma. Tumour Biol. 2013;34:3259–63.CrossRefPubMedGoogle Scholar
  21. 21.
    Hiwasa T, Tokita H, Ike Y. Differential chemosensitivity in oncogene-transformed cells. J Exp Ther Oncol. 1996;1:162–70.PubMedGoogle Scholar
  22. 22.
    Vogt U, Falkiewicz B, Bielawski K, Bosse U, Schlotter CM. Relationship of c-myc and erbB oncogene family gene aberrations and other selected factors to ex vivo chemosensitivity of ovarian cancer in the modified ATP-chemosensitivity assay. Acta Biochim Pol. 2000;47:157–64.PubMedGoogle Scholar
  23. 23.
    Falkiewicz B, Schlotter CM, Bosse U, Bielawski K, Vogt U. c-myc oncogene gene dosage, serum CEA and CA-15.3 antigen levels, and cellular DNA values in relation to ex vivo chemosensitivity of primary human breast cancer. Acta Biochim Pol. 2000;47:149–56.PubMedGoogle Scholar
  24. 24.
    Wang Y, Chen X, Hu X, Zhang R, Du Y, Zang W, et al. Enhancement of silencing DNA polymerase β on the radiotherapeutic sensitivity of human esophageal carcinoma cell lines. Tumour Biol. 2014;35(10):10067–74.CrossRefPubMedGoogle Scholar
  25. 25.
    Demple B, Sung JS. Molecular and biological roles of Ape1 protein in mammalian base excision repair. DNA repair (Amst). 2005;4:1442–9.CrossRefGoogle Scholar
  26. 26.
    McCullough AK, Dodson ML, Lloyd RS. Initiation of base excision repair: glycosylase mechanisms and structures. Annu Rev Biochem. 1999;68:255–85.CrossRefPubMedGoogle Scholar
  27. 27.
    Matsumoto Y, Kim K. Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repair. Science. 1995;269:699–702.CrossRefPubMedGoogle Scholar
  28. 28.
    Starcevic D, Dalal S, Sweasy JB. Is there a link between DNA polymerase beta and cancer? Cell Cycle. 2004;3:998–1001.CrossRefPubMedGoogle Scholar
  29. 29.
    Poltoratsky V, Prasad R, Horton JK, Wilson SH. Down-regulation of DNA polymerase beta accompanies somatic hypermutation in human BL2 cell lines. DNA Repair (Amst). 2007;6:244–53.CrossRefGoogle Scholar
  30. 30.
    Singhal RK, Prasad R, Wilson SH. DNA polymerase beta conducts the gap-filling step in uracil-initiated base excision repair in a bovine testis nuclear extract. J Biol Chem. 1995;270:949–57.CrossRefPubMedGoogle Scholar
  31. 31.
    Sweasy JB, Lang T, DiMaio D. Is base excision repair a tumor suppressor mechanism? Cell Cycle. 2006;5:250–9.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2015

Authors and Affiliations

  • Yuanyuan Wang
    • 1
    • 2
  • Qianqian Sun
    • 1
  • Wei Guo
    • 3
  • Xiaonan Chen
    • 1
  • Yuwen Du
    • 1
  • Wenqiao Zang
    • 1
  • Ziming Dong
    • 1
    • 2
  • Guoqiang Zhao
    • 1
    • 2
  1. 1.College of Basic Medical SciencesZhengzhou UniversityZhengzhouChina
  2. 2.Collaborative Innovation Center of Cancer Chemoprevention of HenanZhengzhouChina
  3. 3.Henan Academy of Medical and Pharmaceutical SciencesZhengzhou UniversityZhengzhouChina

Personalised recommendations