CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection

S. Matsukura, H. Soejima, T. Nakagawachi, H. Yakushiji, A. Ogawa, M. Fukuhara, K. Miyazaki, Y. Nakabeppu, M. Sekiguchi, T. Mukai

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Inactivations of DNA repair genes, O6-methylguanine-DNA methyltransferase (MGMT) and hMLH1, by promoter hypermethylation have been reported in several types of primary human neoplasia. This epigenetic inactivation mechanism remains elusive in hepatocellular carcinoma (HCC). To investigate the relation between the expression of MGMT and hMLH1 and the CpG methylation within their promoters in HCCs with or without hepatitis viral infection, we performed immunohistochemistry and urea/bisulphite sequencing on 46 HCCs, corresponding noncancerous tissues, and 20 normal liver tissues. MGMT- and hMLH1-negative HCCs were 60.9% (28 out of 46) and 21.8% (10 out of 46), respectively. HCCs lacking both proteins were 10.9% (five out of 46). The frequency and extent of CpG methylation in the MGMT promoter increased along with hepatitis viral infection and pathological progression. MGMT-negative tumours showed very frequent and widespread methylation in the promoter compared with MGMT-positive tumours. Half of the hMLH1-negative HCCs showed promoter hypermethylation. These data suggested that MGMT gene silencing in a subset of HCCs was likely caused by epigenetic alteration, such as promoter hypermethylation, and that the promoter hypermethylation silenced the hMLH1 gene in half of the hMLH1-negative tumours. A correlation between the promoter methylation status and viral infection, although it was weak, intimated that hepatitis viral infections could play a role in the CpG methylation of the MGMT promoter.

Original languageEnglish
Pages (from-to)521-529
Number of pages9
JournalBritish journal of cancer
Volume88
Issue number4
DOIs
Publication statusPublished - Feb 24 2003

Fingerprint

Methyltransferases
Virus Diseases
DNA Methylation
Hepatitis
Hepatocellular Carcinoma
DNA
Methylation
Epigenomics
Neoplasms
Gene Silencing
DNA Repair
Genes
Urea
Immunohistochemistry
Liver

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Matsukura, S., Soejima, H., Nakagawachi, T., Yakushiji, H., Ogawa, A., Fukuhara, M., ... Mukai, T. (2003). CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection. British journal of cancer, 88(4), 521-529. https://doi.org/10.1038/sj.bjc.6600743

CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection. / Matsukura, S.; Soejima, H.; Nakagawachi, T.; Yakushiji, H.; Ogawa, A.; Fukuhara, M.; Miyazaki, K.; Nakabeppu, Y.; Sekiguchi, M.; Mukai, T.

In: British journal of cancer, Vol. 88, No. 4, 24.02.2003, p. 521-529.

Research output: Contribution to journalArticle

Matsukura, S, Soejima, H, Nakagawachi, T, Yakushiji, H, Ogawa, A, Fukuhara, M, Miyazaki, K, Nakabeppu, Y, Sekiguchi, M & Mukai, T 2003, 'CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection', British journal of cancer, vol. 88, no. 4, pp. 521-529. https://doi.org/10.1038/sj.bjc.6600743
Matsukura, S. ; Soejima, H. ; Nakagawachi, T. ; Yakushiji, H. ; Ogawa, A. ; Fukuhara, M. ; Miyazaki, K. ; Nakabeppu, Y. ; Sekiguchi, M. ; Mukai, T. / CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection. In: British journal of cancer. 2003 ; Vol. 88, No. 4. pp. 521-529.
@article{19a0cbad084b45edb2448aca3d938939,
title = "CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection",
abstract = "Inactivations of DNA repair genes, O6-methylguanine-DNA methyltransferase (MGMT) and hMLH1, by promoter hypermethylation have been reported in several types of primary human neoplasia. This epigenetic inactivation mechanism remains elusive in hepatocellular carcinoma (HCC). To investigate the relation between the expression of MGMT and hMLH1 and the CpG methylation within their promoters in HCCs with or without hepatitis viral infection, we performed immunohistochemistry and urea/bisulphite sequencing on 46 HCCs, corresponding noncancerous tissues, and 20 normal liver tissues. MGMT- and hMLH1-negative HCCs were 60.9{\%} (28 out of 46) and 21.8{\%} (10 out of 46), respectively. HCCs lacking both proteins were 10.9{\%} (five out of 46). The frequency and extent of CpG methylation in the MGMT promoter increased along with hepatitis viral infection and pathological progression. MGMT-negative tumours showed very frequent and widespread methylation in the promoter compared with MGMT-positive tumours. Half of the hMLH1-negative HCCs showed promoter hypermethylation. These data suggested that MGMT gene silencing in a subset of HCCs was likely caused by epigenetic alteration, such as promoter hypermethylation, and that the promoter hypermethylation silenced the hMLH1 gene in half of the hMLH1-negative tumours. A correlation between the promoter methylation status and viral infection, although it was weak, intimated that hepatitis viral infections could play a role in the CpG methylation of the MGMT promoter.",
author = "S. Matsukura and H. Soejima and T. Nakagawachi and H. Yakushiji and A. Ogawa and M. Fukuhara and K. Miyazaki and Y. Nakabeppu and M. Sekiguchi and T. Mukai",
year = "2003",
month = "2",
day = "24",
doi = "10.1038/sj.bjc.6600743",
language = "English",
volume = "88",
pages = "521--529",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "4",

}

TY - JOUR

T1 - CpG methylation of MGMT and hMLH1 promoter in hepatocellular carcinoma associated with hepatitis viral infection

AU - Matsukura, S.

AU - Soejima, H.

AU - Nakagawachi, T.

AU - Yakushiji, H.

AU - Ogawa, A.

AU - Fukuhara, M.

AU - Miyazaki, K.

AU - Nakabeppu, Y.

AU - Sekiguchi, M.

AU - Mukai, T.

PY - 2003/2/24

Y1 - 2003/2/24

N2 - Inactivations of DNA repair genes, O6-methylguanine-DNA methyltransferase (MGMT) and hMLH1, by promoter hypermethylation have been reported in several types of primary human neoplasia. This epigenetic inactivation mechanism remains elusive in hepatocellular carcinoma (HCC). To investigate the relation between the expression of MGMT and hMLH1 and the CpG methylation within their promoters in HCCs with or without hepatitis viral infection, we performed immunohistochemistry and urea/bisulphite sequencing on 46 HCCs, corresponding noncancerous tissues, and 20 normal liver tissues. MGMT- and hMLH1-negative HCCs were 60.9% (28 out of 46) and 21.8% (10 out of 46), respectively. HCCs lacking both proteins were 10.9% (five out of 46). The frequency and extent of CpG methylation in the MGMT promoter increased along with hepatitis viral infection and pathological progression. MGMT-negative tumours showed very frequent and widespread methylation in the promoter compared with MGMT-positive tumours. Half of the hMLH1-negative HCCs showed promoter hypermethylation. These data suggested that MGMT gene silencing in a subset of HCCs was likely caused by epigenetic alteration, such as promoter hypermethylation, and that the promoter hypermethylation silenced the hMLH1 gene in half of the hMLH1-negative tumours. A correlation between the promoter methylation status and viral infection, although it was weak, intimated that hepatitis viral infections could play a role in the CpG methylation of the MGMT promoter.

AB - Inactivations of DNA repair genes, O6-methylguanine-DNA methyltransferase (MGMT) and hMLH1, by promoter hypermethylation have been reported in several types of primary human neoplasia. This epigenetic inactivation mechanism remains elusive in hepatocellular carcinoma (HCC). To investigate the relation between the expression of MGMT and hMLH1 and the CpG methylation within their promoters in HCCs with or without hepatitis viral infection, we performed immunohistochemistry and urea/bisulphite sequencing on 46 HCCs, corresponding noncancerous tissues, and 20 normal liver tissues. MGMT- and hMLH1-negative HCCs were 60.9% (28 out of 46) and 21.8% (10 out of 46), respectively. HCCs lacking both proteins were 10.9% (five out of 46). The frequency and extent of CpG methylation in the MGMT promoter increased along with hepatitis viral infection and pathological progression. MGMT-negative tumours showed very frequent and widespread methylation in the promoter compared with MGMT-positive tumours. Half of the hMLH1-negative HCCs showed promoter hypermethylation. These data suggested that MGMT gene silencing in a subset of HCCs was likely caused by epigenetic alteration, such as promoter hypermethylation, and that the promoter hypermethylation silenced the hMLH1 gene in half of the hMLH1-negative tumours. A correlation between the promoter methylation status and viral infection, although it was weak, intimated that hepatitis viral infections could play a role in the CpG methylation of the MGMT promoter.

UR - http://www.scopus.com/inward/record.url?scp=0037463277&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037463277&partnerID=8YFLogxK

U2 - 10.1038/sj.bjc.6600743

DO - 10.1038/sj.bjc.6600743

M3 - Article

C2 - 12592365

AN - SCOPUS:0037463277

VL - 88

SP - 521

EP - 529

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 4

ER -