Full Text:   <901>

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CLC number: R36

On-line Access: 2017-09-05

Received: 2016-07-09

Revision Accepted: 2016-10-26

Crosschecked: 2017-08-16

Cited: 0

Clicked: 1661

Citations:  Bibtex RefMan EndNote GB/T7714


Yi-ping Tian


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Journal of Zhejiang University SCIENCE B 2017 Vol.18 No.9 P.747-756


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

Author(s):  Yi-ping Tian, Ai-fen Lin, Mei-fu Gan, Hao Wang, Dan Yu, Chong Lai, Dan-dan Zhang, Yi-min Zhu, Mao-de Lai

Affiliation(s):  Department of Pathology, School of Medicine, Zhejiang University, Hangzhou 310058, China; more

Corresponding email(s):   zhuym@zju.edu.cn, lmd@zju.edu.cn

Key Words:  5-Hydroxymethylcytosine (5hmC), 5-Methylcytosine (5mC), Prognosis, Colorectal cancer

Yi-ping Tian, Ai-fen Lin, Mei-fu Gan, Hao Wang, Dan Yu, Chong Lai, Dan-dan Zhang, Yi-min Zhu, Mao-de Lai. Global changes of 5-hydroxymethylcytosine and 5-methylcytosine from normal to tumor tissues are associated with carcinogenesis and prognosis in colorectal cancer[J]. Journal of Zhejiang University Science B, 2017, 18(9): 747-756.

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author="Yi-ping Tian, Ai-fen Lin, Mei-fu Gan, Hao Wang, Dan Yu, Chong Lai, Dan-dan Zhang, Yi-min Zhu, Mao-de Lai",
journal="Journal of Zhejiang University Science B",
publisher="Zhejiang University Press & Springer",

%0 Journal Article
%T Global changes of 5-hydroxymethylcytosine and 5-methylcytosine from normal to tumor tissues are associated with carcinogenesis and prognosis in colorectal cancer
%A Yi-ping Tian
%A Ai-fen Lin
%A Mei-fu Gan
%A Hao Wang
%A Dan Yu
%A Chong Lai
%A Dan-dan Zhang
%A Yi-min Zhu
%A Mao-de Lai
%J Journal of Zhejiang University SCIENCE B
%V 18
%N 9
%P 747-756
%@ 1673-1581
%D 2017
%I Zhejiang University Press & Springer
%DOI 10.1631/jzus.B1600314

T1 - Global changes of 5-hydroxymethylcytosine and 5-methylcytosine from normal to tumor tissues are associated with carcinogenesis and prognosis in colorectal cancer
A1 - Yi-ping Tian
A1 - Ai-fen Lin
A1 - Mei-fu Gan
A1 - Hao Wang
A1 - Dan Yu
A1 - Chong Lai
A1 - Dan-dan Zhang
A1 - Yi-min Zhu
A1 - Mao-de Lai
J0 - Journal of Zhejiang University Science B
VL - 18
IS - 9
SP - 747
EP - 756
%@ 1673-1581
Y1 - 2017
PB - Zhejiang University Press & Springer
ER -
DOI - 10.1631/jzus.B1600314

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.




Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article


[1]Barciszewska, A.M., Murawa, D., Gawronska, I., et al., 2007. Analysis of 5-methylcytosine in DNA of breast and colon cancer tissues. IUBMB Life, 59(12):765-770.

[2]Baylin, S.B., Jones, P.A., 2011. A decade of exploring the cancer epigenome-biological and translational implications. Nat. Rev. Cancer, 11(10):726-734.

[3]Bird, A., 2002. DNA methylation patterns and epigenetic memory. Gene Dev., 16(1):6-21.

[4]Chen, C.C., Wang, K.Y., Shen, C.K., 2012. The mammalian de novo DNA methyltransferases DNMT3A and DNMT3B are also DNA 5-hydroxymethylcytosine dehydroxymethylases. J. Biol. Chem., 287(40):33116-33121.

[5]Chen, M.L., Shen, F., Huang, W., et al., 2013. Quantification of 5-methylcytosine and 5-hydroxymethylcytosine in genomic DNA from hepatocellular carcinoma tissues by capillary hydrophilic-interaction liquid chromatography/quadrupole TOF mass spectrometry. Clin. Chem., 59(5):824-832.

[6]Dawson, M.A., Kouzarides, T., 2012. Cancer epigenetics: from mechanism to therapy. Cell, 150(1):12-27.

[7]de Smet, C., Loriot, A., 2010. DNA hypomethylation in cancer: epigenetic scars of a neoplastic journey. Epigenetics, 5(3):206-213.

[8]de Smet, C., Loriot, A., 2013. DNA hypomethylation and activation of germline-specific genes in cancer. Adv. Exp. Med. Biol., 754:149-166.

[9]Feinberg, A.P., Gehrke, C.W., Kuo, K.C., et al., 1988. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res., 48(5):1159-1161.

[10]Ficz, G., Branco, M.R., Seisenberger, S., et al., 2011. Dynamic regulation of 5-hydroxymethylcytosine in mouse ES cells and during differentiation. Nature, 473(7347):398-402.

[11]Frigola, J., Sole, X., Paz, M.F., et al., 2005. Differential DNA hypermethylation and hypomethylation signatures in colorectal cancer. Hum. Mol. Genet., 14(2):319-326.

[12]Haffner, M.C., Chaux, A., Meeker, A.K., et al., 2011. Global 5-hydroxymethylcytosine content is significantly reduced in tissue stem/progenitor cell compartments and in human cancers. Oncotarget, 2(8):627-637.

[13]Jin, S.G., Kadam, S., Pfeifer, G.P., 2010. Examination of the specificity of DNA methylation profiling techniques towards 5-methylcytosine and 5-hydroxymethylcytosine. Nucleic Acids Res., 38(11):e125.

[14]Jin, S.G., Jiang, Y., Qiu, R., et al., 2011. 5-hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res., 71(24):7360-7365.

[15]Kohli, R.M., Zhang, Y., 2013. TET enzymes, TDG and the dynamics of DNA demethylation. Nature, 502(7472):472-479.

[16]Kriaucionis, S., Heintz, N., 2009. The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science, 324(5929):929-930.

[17]Kroeze, L.I., Aslanyan, M.G., van Rooij, A., et al., 2014. Characterization of acute myeloid leukemia based on levels of global hydroxymethylation. Blood, 124(7):1110-1118.

[18]Kudo, Y., Tateishi, K., Yamamoto, K., et al., 2012. Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. Cancer Sci., 103(4):670-676.

[19]Larson, A.R., Dresser, K.A., Zhan, Q., et al., 2014. Loss of 5-hydroxymethylcytosine correlates with increasing morphologic dysplasia in melanocytic tumors. Modern Pathol., 27(7):936-944.

[20]Li, J., Huang, Q., Zeng, F., et al., 2014. The prognostic value of global DNA hypomethylation in cancer: a meta-analysis. PLoS ONE, 9(9):e106290.

[21]Li, W., Liu, M., 2011. Distribution of 5-hydroxymethylcytosine in different human tissues. J. Nucleic Acids, 2011:870726.

[22]Lian, C.G., Xu, Y., Ceol, C., et al., 2012. Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell, 150(6):1135-1146.

[23]Liang, J.Z., Li, Y.H., Zhang, Y., et al., 2015. Expression of ETV6/TEL is associated with prognosis in non-small cell lung cancer. Int. J. Clin. Exp. Pathol., 8(3):2937-2945.

[24]Liu, W.R., Tian, M.X., Jin, L., et al., 2014. High expression of 5-hydroxymethylcytosine and isocitrate dehydrogenase 2 is associated with favorable prognosis after curative resection of hepatocellular carcinoma. J. Exp. Clin. Cancer Res., 33:32.

[25]Morikawa, T., Kuchiba, A., Qian, Z.R., et al., 2012. Prognostic significance and molecular associations of tumor growth pattern in colorectal cancer. Ann. Surg. Oncol., 19(6):1944-1953.

[26]Ogino, S., Nosho, K., Kirkner, G.J., et al., 2008. A cohort study of tumoral LINE-1 hypomethylation and prognosis in colon cancer. J. Natl. Cancer Inst., 100(23):1734-1738.

[27]Pfeifer, G.P., Kadam, S., Jin, S.G., 2013. 5-Hydroxymethylcytosine and its potential roles in development and cancer. Epigenet. Chromatin, 6(1):10.

[28]Robertson, K.D., 2005. DNA methylation and human disease. Nat. Rev. Genet., 6(8):597-610.

[29]Robertson, J., Robertson, A.B., Klungland, A., 2011. The presence of 5-hydroxymethylcytosine at the gene promoter and not in the gene body negatively regulates gene expression. Biochem. Bioph. Res. Commun., 411(1):40-43.

[30]Sun, M., Song, C.X., Huang, H., et al., 2013. HMGA2/TET1/HOXA9 signaling pathway regulates breast cancer growth and metastasis. Proc. Natl. Acad. Sci. USA, 110(24):9920-9925.

[31]Sunami, E., de Maat, M., Vu, A., et al., 2011. LINE-1 hypomethylation during primary colon cancer progression. PLoS ONE, 6(4):e18884.

[32]Suzuki, K., Suzuki, I., Leodolter, A., et al., 2006. Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. Cancer Cell, 9(3):199-207.

[33]Turek-Plewa, J., Jagodzinski, P.P., 2005. The role of mammalian DNA methyltransferases in the regulation of gene expression. Cell. Mol. Biol. Lett., 10(4):631-647.

[34]Uribe-Lewis, S., Stark, R., Carroll, T., et al., 2015. 5-Hydroxymethylcytosine marks promoters in colon that resist DNA hypermethylation in cancer. Genome Biol., 16(1):69.

[35]van Engeland, M., Derks, S., Smits, K.M., et al., 2011. Colorectal cancer epigenetics: complex simplicity. J. Clin. Oncol., 29(10):1382-1391.

[36]Wang, J., Tang, J., Lai, M., et al., 2014. 5-Hydroxymethylcytosine and disease. Mutat. Res.-Rev. Mutat., 762:167-175.

[37]Yamada, Y., Jackson-Grusby, L., Linhart, H., et al., 2005. Opposing effects of DNA hypomethylation on intestinal and liver carcinogenesis. Proc. Natl. Acad. Sci. USA, 102(38):13580-13585.

[38]Zhang, L.T., Zhang, L.J., Zhang, J.J., et al., 2013. Quantification of the sixth DNA base 5-hydroxymethylcytosine in colorectal cancer tissue and C-26 cell line. Bioanalysis, 5(7):839-845.

[39]Zheng, Z., Chen, T., Li, X., et al., 2007. DNA synthesis and repair genes RRM1 and ERCC1 in lung cancer. N. Engl. J. Med., 356(8):800-808.

[40]Zhu, X., You, Y., Li, Q., et al., 2014. BCR-ABL1-positive microvesicles transform normal hematopoietic transplants through genomic instability: implications for donor cell leukemia. Leukemia, 28(8):1666-1675.

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