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Aberrant Methylation of Different DNA Repair Genes Demonstrates Distinct Prognostic Value for Esophageal Cancer

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Abstract

Background

DNA mismatch repair (MMR) deficiency results in a strong mutator phenotype and high-frequency microsatellite instability (MSI-H), which are the hallmarks of many tumors.

Aim

The objective of this study is to investigate the promoter CpG island methylation status of mismatch repair genes human mutL homolog 1 (hMLH1), human mutS homolog 2 (hMSH2), and O6-methylguanine-DNA methyltransferase (MGMT) in esophageal squamous cell carcinoma (ESCC) and its roles in alkylating agents chemotherapy.

Methods

Real-time methylation-specific polymerase chain reaction (PCR) (real-time MSP) was employed to detect promoter CpG island methylation of the hMLH1, hMSH2, as well as MGMT genes in 235 surgical tumor tissue samples from ESCC patients and their corresponding normal tissue samples.

Results

Promoter CpG island methylation of hMLH1, hMSH2, and MGMT were detectable in 43.4, 28.9, and 40.4% of ESCC tumor DNA, respectively, and the loss rates of hMLH1, hMSH2, and MGMT protein expression were 48.6, 34.5, and 40.9% in tumor tissues, respectively. For the entire population of 235 ESCC patients who were enrolled in operating treatment combined with radiotherapy and chemotherapy with alkylating agents, there was a significant difference in the overall survival between patients with methylated MGMT promoter and those with an unmethylated MGMT promoter (P < 0.05).

Conclusion

Promoter CpG island methylation may be a frequent event in ESCC carcinogenesis. Detection of the methylated sequences of hMLH1, hMSH2, and MGMT appears to be promising as a predictive factor in primary ESCC.

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Acknowledgments

This research was partly supported by two grants from the Natural Science Foundation of Zhejiang Province, China (No. Y2080749 and No. Y2091110), a grant from the Zhejiang Province Science and Technology Fund for excellent returnee (No. 2008004), a grant from the Science and Technology General Project of Zhejiang Province (No. 2009C33143), a grant from the Ministry of Education Science and Technology Fund for Excellent Returnee, China (No. 2010609), a grant from the Scientific and Technological Innovations Fund of Henan Province Higher Education (No. 2009HAST1T001), and a grant from the Science and Technology Key Project of the Ministry of Education, China (No. 210130).

Conflicts of interest

The authors declare that they have no conflicts of interest.

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Authors and Affiliations

  1. Zhejiang Cancer Research Institute, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, No. 38 Guangji Rd., Banshanqiao District, 310022, Hangzhou, People’s Republic of China

    Zhi-Qiang Ling & Wei-Min Mao

  2. Department of Pathophysiology, College of Medical Sciences, Zhengzhou University, 450052, Zhengzhou, People’s Republic of China

    Pei Li & Zi-Min Dong

  3. Department of Tumor Surgery, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, No. 38 Guangji Rd., Banshanqiao District, 310022, Hangzhou, People’s Republic of China

    Ming-Hua Ge

  4. Department of Radiotherapy, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, No. 38 Guangji Rd., Banshanqiao District, 310022, Hangzhou, People’s Republic of China

    Fu-Jun Hu

  5. Department of Pathology, Zhejiang Province Cancer Hospital, Zhejiang Cancer Center, No. 38 Guangji Rd., Banshanqiao District, 310022, Hangzhou, People’s Republic of China

    Xian-Hua Fang

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  1. Zhi-Qiang Ling
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Ling, ZQ., Li, P., Ge, MH. et al. Aberrant Methylation of Different DNA Repair Genes Demonstrates Distinct Prognostic Value for Esophageal Cancer. Dig Dis Sci 56, 2992–3004 (2011). https://doi.org/10.1007/s10620-011-1774-z

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  • DOI: https://doi.org/10.1007/s10620-011-1774-z

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