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DNA polymerase ζ as a potential biomarker of chemoradiation resistance and poor prognosis for cervical cancer

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Abstract

DNA Polymerase ζ (Polζ), an error-prone DNA polymerase involved in translesion DNA synthesis, plays a significant role in the cytotoxicity, mutagenicity, and chemoresistance of several cancers. To evaluate the association of Polζ with chemoradiation resistance and prognosis in cervical cancer, we enrolled 123 patients with squamous cell carcinoma of cervical cancer, who had adjuvant concurrent chemoradiation therapy after radical surgery treated at Fudan University Shanghai Cancer Center between 2008 and 2009, and tested their in vitro tumor inhibition rates using the 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide method and Polζ protein expression in paraffin-embedded tissues using immunohistochemistry. We found that the Polζ-positive expression was detected in 22 % of the cases. The median in vitro inhibition rate of tumor cell growth by cisplatin, carboplatin, nedaplatin, and oxaliplatin was 80, 37, 78, and 51 %, respectively. Among the tumor-related variables, FIGO stage, tumor grade, and Polζ protein expression (adjusted HR 6.7, 4.2 and 6.7; 95 % CI 1.7–26.3, 1.0–17.3 and 1.8–25.4; P = 0.007, 0.046 and 0.005, respectively) were found to be significant predictors for recurrence. Kaplan–Meier survival estimates showed that the patients with more advanced stage (IIB) or Polζ-positive expression had a significantly shorter progression-free survival. Polζ-positive expression was significantly associated with depth of cervical stromal invasion (P = 0.012). However, the association between Polζ expression and in vitro tumor inhibition rates was not significant. Taken together, Polζ expression can be used as the predictor for poor prognosis, which might be caused by the potential chemoradiation resistance of the cervical cancer patients. The mechanism deserves further exploration.

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Abbreviations

Polζ:

DNA polymerase ζ

CSCC:

Squamous cell carcinoma of cervical cancer

TLS:

Translesion DNA synthesis

NER:

Nucleotide excision repair

IHC:

Immunohistochemistry

TMA:

Tissue microarray

MTT:

3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide

FIGO:

International Federation of Gynecology and Obstetrics

LN:

Lymph node

LVSI:

Lympho-vascular space invasion

OD:

Optical density

PFS:

Progression-free survival

OS:

Overall survival

HR:

Hazard ratio

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Acknowledgments

This study was supported by Science Foundation for Young Scholars of Fudan University and accepted for oral presentation in IGCS 2012 meeting. We would like to thank Yunhua Lin, Guangqi Qin, and Hongyu Gu of Fudan University Shanghai Cancer Center for performing in vitro MTT assay, tissue microarray, and immunohistochemistry techniques, respectively, and thank Professor Shaokang Zhan of Fudan University School of Public Health for statistical analysis support. We also would like to thank Dr. Robert L. Coleman of M. D. Anderson Cancer Center for reviewing this paper.

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Authors and Affiliations

  1. Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    Ting-Yan Shi, Gong Yang & Qingyi Wei

  2. Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, 270 Dongan Road, Shanghai, 200032, China

    Ting-Yan Shi, Li Yang, **aohua Wu & ** Cheng

  3. Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China

    **ao-Yu Tu

  4. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China

    Ting-Yan Shi, Li Yang, Gong Yang, **ao-Yu Tu, **aohua Wu & ** Cheng

  5. National Population and Family Planning Key Laboratory of Contraceptive Drugs & Devices, Shanghai Institute of Planned Parenthood Research, Shanghai, 200032, China

    Ting-Yan Shi

  6. Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    Qingyi Wei

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  1. Ting-Yan Shi
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  2. Li Yang
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  7. Qingyi Wei
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Corresponding author

Correspondence to ** Cheng.

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Ting-Yan Shi and Li Yang contributed equally to this work.

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Shi, TY., Yang, L., Yang, G. et al. DNA polymerase ζ as a potential biomarker of chemoradiation resistance and poor prognosis for cervical cancer. Med Oncol 30, 500 (2013). https://doi.org/10.1007/s12032-013-0500-4

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  • DOI: https://doi.org/10.1007/s12032-013-0500-4

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