Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Journal of Experimental & Clinical Cancer Research
Published in: Journal of Experimental & Clinical Cancer Research 1/2014

Open Access 01-12-2014 | Research

High expression of 5-hydroxymethylcytosine and isocitrate dehydrogenase 2 is associated with favorable prognosis after curative resection of hepatocellular carcinoma

Authors: Wei-Ren Liu, Meng-Xin Tian, Lei Jin, Liu-Xiao Yang, Zhen-Bin Ding, Ying-Hao Shen, Yuan-Fei Peng, Jian Zhou, Shuang-Jian Qiu, Zhi Dai, Jia Fan, Ying-Hong Shi

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2014

Login to get access

Abstract

Background

The expression of 5-hydroxymethylcytosine (5-hmC) and isocitrate dehydrogenase 2 (IDH2) is frequently downregulated in numerous cancers. 5-hmC and IDH2 expression in hepatocellular carcinoma (HCC) has yet to be determined.

Methods

The immunohistochemical expression of 5-hmC and IDH2 were analyzed in tissue microarrays containing samples from 646 patients who had undergone hepatectomy for histologically proven HCC. The prognostic value of 5-hmC and IDH2 were evaluated by Cox regression and Kaplan-Meier analyses.

Results

We discovered that low 5-hmC and IDH2 expression was associated with malignant behaviors. Low 5-hmC or IDH2 expression alone and combined 5-hmC and IDH2 expression were associated with lower overall survival (OS) rates and higher cumulative recurrence rates. Multivariate analysis indicated that 5-hmC or IDH2 and 5-hmC/IDH2 were independent prognostic indicators for OS and time to recurrence (TTR), which was confirmed in an independent validation cohort.

Conclusions

5-hmC and IDH2 correlate with less aggressive tumor behavior in HCC. When 5-hmC and IDH2 are considered together, they serve as a prognostic marker in patients with surgically resected HCCs.
Appendix
Available only for authorised users
Literature
1.
2.
Maluccio M, Covey A: Recent progress in understanding, diagnosing, and treating hepatocellular carcinoma. CA Cancer J Clin. 2012, 62: 394-399. 10.3322/caac.21161.CrossRefPubMed
3.
Rodriguez-Paredes M, Esteller M: Cancer epigenetics reaches mainstream oncology. Nat Med. 2011, 17: 330-339.CrossRefPubMed
4.
Liu WR, Shi YH, Peng YF, Fan J: Epigenetics of hepatocellular carcinoma: a new horizon. Chin Med J. 2012, 125: 2349-2360.PubMed
5.
Berdasco M, Esteller M: Aberrant epigenetic landscape in cancer: how cellular identity goes awry. Dev Cell. 2010, 19: 698-711. 10.1016/j.devcel.2010.10.005.CrossRefPubMed
6.
Liu X, Chen X, Yu X, Tao Y, Bode AM, Dong Z, Cao Y: Regulation of microRNAs by epigenetics and their interplay involved in cancer. J Exp Clin Cancer Res. 2013, 32: 96-10.1186/1756-9966-32-96.PubMedCentralCrossRefPubMed
7.
Tahiliani M, Koh KP, Shen Y, Pastor WA, Bandukwala H, Brudno Y, Agarwal S, Iyer LM, Liu DR, Aravind L, Rao A: Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science. 2009, 324: 930-935. 10.1126/science.1170116.PubMedCentralCrossRefPubMed
8.
Kriaucionis S, Heintz N: The nuclear DNA base 5-hydroxymethylcytosine is present in Purkinje neurons and the brain. Science. 2009, 324: 929-930. 10.1126/science.1169786.PubMedCentralCrossRefPubMed
9.
Ito S, D’Alessio AC, Taranova OV, Hong K, Sowers LC, Zhang Y: Role of Tet proteins in 5mC to 5hmC conversion, ES-cell self-renewal and inner cell mass specification. Nature. 2010, 466: 1129-1133. 10.1038/nature09303.PubMedCentralCrossRefPubMed
10.
Szwagierczak A, Bultmann S, Schmidt CS, Spada F, Leonhardt H: Sensitive enzymatic quantification of 5-hydroxymethylcytosine in genomic DNA. Nucleic Acids Res. 2010, 38: e181-10.1093/nar/gkq684.PubMedCentralCrossRefPubMed
11.
Lian CG, Xu Y, Ceol C, Wu F, Larson A, Dresser K, Xu W, Tan L, Hu Y, Zhan Q, Lee CW, Hu D, Lian BQ, Kleffel S, Yang Y, Neiswender J, Khorasani AJ, Fang R, Lezcano C, Duncan LM, Scolyer RA, Thompson JF, Kakavand H, Houvras Y, Zon LI, Mihm MC, Kaiser UB, Schatton T, Woda BA, Murphy GF: Loss of 5-hydroxymethylcytosine is an epigenetic hallmark of melanoma. Cell. 2012, 150: 1135-1146. 10.1016/j.cell.2012.07.033.PubMedCentralCrossRefPubMed
12.
Orr BA, Haffner MC, Nelson WG, Yegnasubramanian S, Eberhart CG: Decreased 5-hydroxymethylcytosine is associated with neural progenitor phenotype in normal brain and shorter survival in malignant glioma. PloS One. 2012, 7: e41036-10.1371/journal.pone.0041036.PubMedCentralCrossRefPubMed
13.
Kudo Y, Tateishi K, Yamamoto K, Yamamoto S, Asaoka Y, Ijichi H, Nagae G, Yoshida H, Aburatani H, Koike K: Loss of 5-hydroxymethylcytosine is accompanied with malignant cellular transformation. Cancer Sci. 2012, 103: 670-676. 10.1111/j.1349-7006.2012.02213.x.CrossRefPubMed
14.
Yang H, Liu Y, Bai F, Zhang JY, Ma SH, Liu J, Xu ZD, Zhu HG, Ling ZQ, Ye D, Guan KL, Xiong Y: Tumor development is associated with decrease of TET gene expression and 5-methylcytosine hydroxylation. Oncogene. 2013, 32: 663-669. 10.1038/onc.2012.67.PubMedCentralCrossRefPubMed
15.
Jin SG, Jiang Y, Qiu R, Rauch TA, Wang Y, Schackert G, Krex D, Lu Q, Pfeifer GP: 5-Hydroxymethylcytosine is strongly depleted in human cancers but its levels do not correlate with IDH1 mutations. Cancer Res. 2011, 71: 7360-7365. 10.1158/0008-5472.CAN-11-2023.PubMedCentralCrossRefPubMed
16.
Chen ML, Shen F, Huang W, Qi JH, Wang Y, Feng YQ, Liu SM, Yuan BF: 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. 2013, 59: 824-832. 10.1373/clinchem.2012.193938.PubMedCentralCrossRefPubMed
17.
Reitman ZJ, Jin G, Karoly ED, Spasojevic I, Yang J, Kinzler KW, He Y, Bigner DD, Vogelstein B, Yan H: Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc Natl Acad Sci U S A. 2011, 108: 3270-3275. 10.1073/pnas.1019393108.PubMedCentralCrossRefPubMed
18.
Wang F, Travins J, DeLaBarre B, Penard-Lacronique V, Schalm S, Hansen E, Straley K, Kernytsky A, Liu W, Gliser C, Yang H, Gross S, Artin E, Saada V, Mylonas E, Quivoron C, Popovici-Muller J, Saunders JO, Salituro FG, Yan S, Murray S, Wei W, Gao Y, Dang L, Dorsch M, Agresta S, Schenkein DP, Biller SA, Su SM, de Botton S: Targeted inhibition of mutant IDH2 in leukemia cells induces cellular differentiation. Science. 2013, 340: 622-626. 10.1126/science.1234769.CrossRefPubMed
19.
20.
Lee D, Kang SY, Suh YL, Jeong JY, Lee JI, Nam DH: Clinicopathologic and genomic features of gliosarcomas. J Neurooncol. 2012, 107: 643-650. 10.1007/s11060-011-0790-3.CrossRefPubMed
21.
Wang Z, Bao Z, Yan W, You G, Wang Y, Li X, Zhang W: Isocitrate dehydrogenase 1 (IDH1) mutation-specific microRNA signature predicts favorable prognosis in glioblastoma patients with IDH1 wild type. J Exp Clin Cancer Res. 2013, 32: 59-10.1186/1756-9966-32-59.PubMedCentralCrossRefPubMed
22.
Xu W, Yang H, Liu Y, Yang Y, Wang P, Kim SH, Ito S, Yang C, Wang P, Xiao MT, Liu LX, Jiang WQ, Liu J, Zhang JY, Wang B, Frye S, Zhang Y, Xu YH, Lei QY, Guan KL, Zhao SM, Xiong Y: Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of alpha-ketoglutarate-dependent dioxygenases. Cancer Cell. 2011, 19: 17-30. 10.1016/j.ccr.2010.12.014.PubMedCentralCrossRefPubMed
23.
Gao Q, Qiu SJ, Fan J, Zhou J, Wang XY, Xiao YS, Xu Y, Li YW, Tang ZY: Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J Clin Oncol. 2007, 25: 2586-2593. 10.1200/JCO.2006.09.4565.CrossRefPubMed
24.
Liao R, Sun J, Wu H, Yi Y, Wang JX, He HW, Cai XY, Zhou J, Cheng YF, Fan J, Qiu SJ: High expression of IL-17 and IL-17RE associate with poor prognosis of hepatocellular carcinoma. J Exp Clin Cancer Res. 2013, 32: 3-10.1186/1756-9966-32-3.PubMedCentralCrossRefPubMed
25.
Sun HC, Zhang W, Qin LX, Zhang BH, Ye QH, Wang L, Ren N, Zhuang PY, Zhu XD, Fan J, Tang ZY: Positive serum hepatitis B e antigen is associated with higher risk of early recurrence and poorer survival in patients after curative resection of hepatitis B-related hepatocellular carcinoma. J Hepatol. 2007, 47: 684-690. 10.1016/j.jhep.2007.06.019.CrossRefPubMed
26.
Shi YH, Ding WX, Zhou J, He JY, Xu Y, Gambotto AA, Rabinowich H, Fan J, Yin XM: Expression of X-linked inhibitor-of-apoptosis protein in hepatocellular carcinoma promotes metastasis and tumor recurrence. Hepatology. 2008, 48: 497-507. 10.1002/hep.22393.PubMedCentralCrossRefPubMed
27.
Ding ZB, Shi YH, Zhou J, Qiu SJ, Xu Y, Dai Z, Shi GM, Wang XY, Ke AW, Wu B, Fan J: Association of autophagy defect with a malignant phenotype and poor prognosis of hepatocellular carcinoma. Cancer Res. 2008, 68: 9167-9175. 10.1158/0008-5472.CAN-08-1573.CrossRefPubMed
28.
Tsukada T, Fushida S, Harada S, Terai S, Yagi Y, Kinoshita J, Oyama K, Tajima H, Fujita H, Ninomiya I, Fujimura T, Ohta T: Adiponectin receptor-1 expression is associated with good prognosis in gastric cancer. J Exp Clin Cancer Res. 2011, 30: 107-10.1186/1756-9966-30-107.PubMedCentralCrossRefPubMed
29.
Li Z, Cai X, Cai CL, Wang J, Zhang W, Petersen BE, Yang FC, Xu M: Deletion of Tet2 in mice leads to dysregulated hematopoietic stem cells and subsequent development of myeloid malignancies. Blood. 2011, 118: 4509-4518. 10.1182/blood-2010-12-325241.PubMedCentralCrossRefPubMed
30.
Zhang C, Moore LM, Li X, Yung WK, Zhang W: IDH1/2 mutations target a key hallmark of cancer by deregulating cellular metabolism in glioma. Neuro Oncol. 2013, 15: 1114-1126. 10.1093/neuonc/not087.PubMedCentralCrossRefPubMed
31.
Wang JH, Chen WL, Li JM, Wu SF, Chen TL, Zhu YM, Zhang WN, Li Y, Qiu YP, Zhao AH, Mi JQ, Jin J, Wang YG, Ma QL, Huang H, Wu DP, Wang QR, Li Y, Yan XJ, Yan JS, Li JY, Wang S, Huang XJ, Wang BS, Jia W, Shen Y, Chen Z, Chen SJ: Prognostic significance of 2-hydroxyglutarate levels in acute myeloid leukemia in China. Proc Natl Acad Sci U S A. 2013, 110: 17017-17022. 10.1073/pnas.1315558110.PubMedCentralCrossRefPubMed
32.
Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, Pollock R, O’Donnell P, Grigoriadis A, Diss T, Eskandarpour M, Presneau N, Hogendoorn PC, Futreal A, Tirabosco R, Flanagan AM: IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011, 224: 334-343. 10.1002/path.2913.CrossRefPubMed
33.
Sia D, Tovar V, Moeini A, Llovet JM: Intrahepatic cholangiocarcinoma: pathogenesis and rationale for molecular therapies. Oncogene. 2013, 32: 4861-4870. 10.1038/onc.2012.617.PubMedCentralCrossRefPubMed
34.
Dawson MA, Kouzarides T: Cancer epigenetics: from mechanism to therapy. Cell. 2012, 150: 12-27. 10.1016/j.cell.2012.06.013.CrossRefPubMed
35.
36.
Metadata
Title
High expression of 5-hydroxymethylcytosine and isocitrate dehydrogenase 2 is associated with favorable prognosis after curative resection of hepatocellular carcinoma
Authors
Wei-Ren Liu
Meng-Xin Tian
Lei Jin
Liu-Xiao Yang
Zhen-Bin Ding
Ying-Hao Shen
Yuan-Fei Peng
Jian Zhou
Shuang-Jian Qiu
Zhi Dai
Jia Fan
Ying-Hong Shi
Publication date
01-12-2014
Publisher
BioMed Central
Published in
Journal of Experimental & Clinical Cancer Research / Issue 1/2014
Electronic ISSN: 1756-9966
DOI
https://doi.org/10.1186/1756-9966-33-32

Other articles of this Issue 1/2014

Journal of Experimental & Clinical Cancer Research 1/2014 Go to the issue

Research

The inhibitory effects of extracellular ATP on the growth of nasopharyngeal carcinoma cells via P2Y2 receptor and osteopontin

Research

Arsenic trioxide induces oxidative stress, DNA damage, and mitochondrial pathway of apoptosis in human leukemia (HL-60) cells

Research

Inhibition of Aurora B by CCT137690 sensitizes colorectal cells to radiotherapy

Research

Clinical implications of high NQO1 expression in breast cancers

Review

Multiple functions of hypoxia-regulated miR-210 in cancer

Research

Promoter methylation of tumor suppressor genes in pre-neoplastic lesions; potential marker of disease recurrence
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits