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Global changes of 5-hydroxymethylcytosine and 5-methylcytosine from normal to tumor tissues are associated with carcinogenesis and prognosis in colorectal cancer

正常组织与肿瘤组织中总体5hmC 和5mC 水平 的变化程度与结直肠癌肿瘤发生及预后有关

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Abstract

Aberrant DNA methylation has raised widespread attention in tumorigenesis. In this study, we aimed to investigate the changes of global DNA methylation and hydroxymethylation from normal to tumor tissues in colorectal cancer (CRC) and their association with the prognosis. The levels of genomic 5-hydroxymethylcytosine (5hmC) and 5-methylcytosine (5mC) in cancerous tissues were significantly lower than those in corresponding adjacent normal tissues. The genomic levels of 5mC were significantly positively correlated with 5hmC in normal and cancerous tissues (all P<0.05). The ratio of 5mC in cancerous tissues to matched normal tissues (C/N-5mC) was also significantly positively correlated with the ratio of 5hmC in cancerous tissues to matched normal tissues (C/N-5hmC) (P=0.01). The 5mC levels and C/N-5mC ratios decreased with age (all P<0.05). Higher 5mC and 5hmC levels were found in rectal than in colon tissues (all P<0.05). High levels of 5mC in cancerous tissues and high C/N-5hmC ratios were each associated with lymph node metastasis (all P<0.05). Survival analysis indicated that the C/N-5mC ratio (P=0.04) is an independent protective factor for overall survival. The data showed that patients with a combination of high C/N-5hmC and low C/N-5mC ratios tended to have a worse prognosis (P<0.01). Our findings showed that the C/N-5mC ratio may be an independent prognostic factor for CRC outcome. Patients with both a high C/N-5hmC ratio and a low C/N-5mC ratio exhibited the worst survival, suggesting that 5mC and 5hmC can be used as critical markers in tumorigenesis and prognosis estimation.

中文概要

目的

研究DNA 总体甲基化、羟甲基化水平与结直肠 癌发生、发展及预后的关系。

创新点

采用肿瘤与正常组织总体5-甲基胞嘧啶(5mC)、 5-羟甲基胞嘧啶(5hmC)的比值并探讨其与结直 肠癌临床病理变化和预后的关系。

方法

采用酶联免疫吸附试验(ELISA)方法检测肿瘤 与相应正常组织基因组中总体5hmC 和5mC 水平。

结论

C/N-5mC 比值的水平对结直肠癌的预后是一个独 立的保护性因子(P=0.04)。当病人同时具有高水 平的C/N-5hmC 和低水平的C/N-5mC,其预后更 差(P<0.01)。因此,可以使用5mC 和5hmC 对 结直肠癌的发生和预后进行评估。

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Acknowledgments

We thank Dr. Iain Charles BRUCE (Department of Physiology, School of Medicine, Zhejiang University, Hangzhou, China) for linguistic review of the manuscript.

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Authors and Affiliations

  1. Department of Pathology, School of Medicine, Zhejiang University, Hangzhou, 310058, China

    Yi-ping Tian, Hao Wang, Dan Yu, Dan-dan Zhang & Mao-de Lai

  2. Key Laboratory of Disease Proteomics of Zhejiang Province, Hangzhou, 310058, China

    Yi-ping Tian, Hao Wang, Dan Yu, Dan-dan Zhang & Mao-de Lai

  3. Pathology Department, Zhejiang Cancer Hospital, Hangzhou, 310022, China

    Yi-ping Tian

  4. Medical Research Center/Human Tissue Bank, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, 317000, China

    Ai-fen Lin

  5. Department of Pathology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical University, Linhai, 317000, China

    Mei-fu Gan

  6. Department of Urology, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003, China

    Chong Lai

  7. Department of Epidemiology and Biostatistics, School of Public Health, Zhejiang University, Hangzhou, 310058, China

    Yi-min Zhu

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  1. Yi-ping Tian
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  2. Ai-fen Lin
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  3. Mei-fu Gan
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  4. Hao Wang
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  7. Dan-dan Zhang
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  8. Yi-min Zhu
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  9. Mao-de Lai
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Correspondence to Yi-min Zhu or Mao-de Lai.

Additional information

Project supported by the 111 Project (No. B13026), the National High-Tech R&D Program (863) of China (No. 2012AA02A601), the Fundamental Research Funds for the Central Universities, and the Zhejiang Provincial Program for the Cultivation of High-Level Innovative Health Talents

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Tian, Yp., Lin, Af., Gan, Mf. et al. Global changes of 5-hydroxymethylcytosine and 5-methylcytosine from normal to tumor tissues are associated with carcinogenesis and prognosis in colorectal cancer. J. Zhejiang Univ. Sci. B 18, 747–756 (2017). https://doi.org/10.1631/jzus.B1600314

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