<i>O</i><sup>6</sup>-Methylguanine-DNA methyltransferase activity in human liver tumors

Isowa, Gohei; Ishizaki, Kanji; Sadamoto, Tetsuo; Tanaka, Kōichi; Yamaoka, Yoshio; Ozawa, Kazue; Ikenaga, Mituo

doi:10.1093/carcin/12.7.1313

Cited by 40 publications

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“…The highest levels of MGMT activity have been described for normal liver tissue. 20 Here, we show that liver metastases from uveal melanoma exhibited an average of 30% of the activity measured in the liver, which is higher than the activity reported from lung and brain tumors with 10-20% of liver activity, respectively. 24,25 Altogether, our data raise the question whether determination of MGMT expression in uveal melanoma metastasis would be helpful for predicting response to alkylating agent therapy.…”

Section: Discussioncontrasting

confidence: 55%

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Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma

Voelter

Diserens

Moulin

et al. 2008

Intl Journal of Cancer

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Uveal melanoma is associated with a high mortality rate once metastases occur, with over >90% of metastatic patients dying within less than 1 year from metastases to the liver. The intraarterial hepatic (iah) administration of the alkylating agent fotemustine holds some promise with response rates of 36% and median survival of 15 months. Here, we investigated whether the DNArepair-protein MGMT may be involved in the variability of response to fotemustine and temozolomide in uveal melanoma. Epigenetic inactivation of MGMT has been demonstrated to be a predictive marker for benefit from alkylating agent therapy in glioblastoma. We found a methylated MGMT promoter in 6% of liver metastases from 34 uveal melanoma patients. The mean MGMT activity measured in liver metastases with negligible liver tissue content was significantly lower than in liver tissue (146 versus 523 fmol/mg protein, p 5 0.002). Expression of the MGMT protein was detectable in 50% of 88 metastases by immunohistochemistry on a tissue microarray. Expression was heterogeneous, and in accordance with MGMT activity data, usually lower than in the surrounding liver. Differential MGMT activity/ expression between metastasis and liver tissue and more efficient depletion of MGMT with higher doses of alkylating agent therapy using iah delivery may provide the pharmacologic window for the higher response rate. However, these results do not support MGMT methylation status or protein expression as predictive markers for treatment outcome to iah chemotherapy with alkylating agents. ' 2008 Wiley-Liss, Inc.Key words: uveal melanoma; liver metastases; MGMT gene silencing; fotemustine Uveal melanoma is a rare disease with an estimated incidence of 0.6 per 100,000 persons/year. At diagnosis, tumors are often at an advanced stage, with 5-year survival rate of almost 50%.1-3 In contrast to its cutaneous counterpart, melanoma of the eye primarily metastasizes hematogenously, with a particular tropism to the liver, thus displaying distinct biological and clinical features. 4,5 Once liver metastases are diagnosed, patients usually die within less than 1 year, and standard systemic chemotherapy regimens are often ineffective with response rates below 10%. Locoregional intraarterial hepatic (iah) chemotherapy has demonstrated some promise. Recently, we have reported the updated results of our previous phase II trial in a series of over 100 patients demonstrating that the 3rd generation chloroethylnitrosurea fotemustine leads to significant disease control when administered directly into the hepatic artery. 6,7 Response rate was 36%, and even more importantly the median overall survival was 15 months and 29% of the patients were alive at 2 years.An important role for resistance to alkylating agent therapy has been attributed to the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT) (reviewed by Gerson).8 MGMT removes the alkyl groups from the O 6 -position of guanine, an important site of DNA alkylation, thereby blunting the therapeutic effect of DNA-alkylat...

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Section: Discussioncontrasting

confidence: 55%

“…Since liver is known for high MGMT activity, 20 we estimated the percentage of normal liver content by histology for each sample. A linear mixed-effect model was fitted to estimate the activity in the metastasis in comparison to liver tissue, taking into account the different degree of liver content they comprised.…”

Section: Resultsmentioning

confidence: 99%

Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma

Voelter

Diserens

Moulin

et al. 2008

Intl Journal of Cancer

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“…Consistent with these results, a previous study of enzyme activity in HCC found that 6 of 21 (30%) tumors had Ͼ3-fold less activity compared to adjacent normal tissues. 29 While MGMT methylation correlated well with MGMT expression, 5 samples (6%) gave discordant data (Table I). Because tissue sections were not microdissected, detection of MGMT hypermethylation may be affected by contamination of tumor with adjacent nontumor tissue cells.…”

Section: Discussionmentioning

confidence: 93%

Inactivation of the DNA repair gene O⁶‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B₁‐DNA adducts and p53 mutation in hepatocellular carcinoma

Zhang

Chen

Ahsan

et al. 2002

Intl Journal of Cancer

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Hepatocellular carcinoma (HCC) is one of the most common human malignant neoplasms with almost 500,000 estimated new cases enumerated worldwide during the most recent year surveyed. 1 Its etiology is not completely clear, but strong associations exist with hepatitis B and C virus infection and several dietary or environmental factors, including aflatoxin B 1 (AFB 1 ). The molecular pathogenesis of HCC appears to involve multiple genetic aberrations in the molecular control of hepatocyte proliferation, differentiation and death and the maintenance of genomic integrity. This process is influenced by the cumulative activation and inactivation of oncogenes, tumor suppressor genes and other genes. 0 6 -methylguanine-DNA methyltransferase (MGMT) is a 22,000 kd protein that is critical for the rapid reversal of methylation of guanine. 2,3 Alkylation of DNA at the O 6 position of guanine is a potentially mutagenic lesion mainly due to the tendency of O 6 -methylguanine to pair with thymine during replication, resulting in the conversion of a guanine-cytosine to an adenine-thymine base pair. 4 The level of MGMT activity varies greatly between species and cell types. 5,6 In humans, liver contains the highest level of MGMT activity. 5 The amounts of MGMT protein are decreased in some tumors and tumor cell lines. 7,8 Loss of expression is rarely due to deletion, mutation or rearrangement of the MGMT gene, but methylation of a discrete region of the CpG island of MGMT has been associated with the silencing of the gene in cell lines. 9 -11 Hypermethylation of normally unmethylated CpG islands in the promoter regions of many genes correlates with loss of transcription. 12 Early MGMT inactivation has been linked with gene mutation in some critical growth regulatory genes; K-ras mutations, especially G to A, are more common in colon cancer after MGMT inactivation. 13 Inactivation of the MGMT gene by promoter hypermethylation has been found in brain tumors, colon cancer, lung cancer and other cancers. 2 Recently, it was reported that MGMT promoter hypermethylation was present significantly more often in tumors with a G to A mutation in p53 than in tumors with other types of p53 mutation or in tumors with wild-type p53. 14,15 In our study, we explored the possible role of inactivation of MGMT in the development of HCC. We had previously analyzed these samples for p53 gene and protein alterations as well as measured DNA damage levels caused by the dietary carcinogen AFB 1 . 16 More recently, we reported a high frequency of promoter hypermethylation of the human ras association domain family 1A (RASSF1A) gene in HCC. 17 Thus, we also investigated the relationship between these biomarkers and methylation status.

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“…Human hepatocellular carcinoma has been linked with hepatitis exposure, cirrhosis, aflatoxin exposure, and iron overload (44)(45)(46), and recent trends indicate an increasing prevalence of hepatocellular carcinoma in humans (47). A link between O 6 mG and hepatocellular carcinoma was suggested by the reduced MGMT activity observed in 38% of 21 human liver tumors (23). The significant reduction in the prevalence of spontaneous hepatocellular carcinoma in males from three independent lines of transgenic mice overexpressing hMGMT in liver that we observed in this study supports a link between spontaneous O 6 mG lesions in the etiology of hepatocellular carcinoma.…”

Section: Discussionmentioning

confidence: 99%

“…By ''spontaneous'' we mean that the source of the methylation of G is not known. Isowa et al (23) reported that eight of 21 human liver tumor samples had reduced or undetectable MGMT activity relative to adjacent normal liver tissue, thereby suggesting the O 6 mG lesion may be important in human liver tumorigenesis. We have tested this hypothesis in a mouse model system.…”

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confidence: 99%

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O ⁶ - methylguanine-DNA methyltransferase

Zhou

Manguino

Kewitt

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

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O 6 -methylguanine (O 6 mG) is a potent mutagenic and procarcinogenic DNA lesion. Organisms have evolved with a DNA repair mechanism that largely ameliorates the deleterious effects of O 6 mG through a direct reversal mechanism by a protein termed O 6 -methylguanine-DNA methyltransferase (MGMT). However, the contribution of O 6 mG to carcinogenesis, in the absence of known exposure to agents that produce it, has not been defined. Nontransgenic C3HeB male mice have a high frequency of spontaneous liver tumors. Transgenic CeHeB͞FeJ mice expressing human MGMT (hMGMT) were generated that had elevated hepatic MGMT activity. The spontaneous development of hepatocellular carcinoma was significantly reduced in those mice expressing hMGMT compared with nontransgenic C3HeB͞FeJ male mice. No differences were detected in spontaneous mutant frequencies in lacI transgenes in mice carrying hMGMT compared with that without hMGMT but the proportion of GC to AT transition mutations was lower in the transgenic mice carrying hMGMT as well as lacI. Tumors that arose in C3HeB͞FeJ transgenic mice were largely deficient in hMGMT protein as determined by immunohistochemistry with a monoclonal antibody directed against hMGMT. Together these data indicate that spontaneous O 6 mG lesions induced hepatocellular carcinogenesis in C3HeB͞FeJ male mice. These transgenic mice represent a rare example of reduced spontaneous carcinogenesis.

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O⁶-Methylguanine-DNA methyltransferase activity in human liver tumors

Cited by 40 publications

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Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma

Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma

Inactivation of the DNA repair gene O⁶‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B₁‐DNA adducts and p53 mutation in hepatocellular carcinoma

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O ⁶ - methylguanine-DNA methyltransferase

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O6-Methylguanine-DNA methyltransferase activity in human liver tumors

Cited by 40 publications

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Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma

Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma

Inactivation of the DNA repair gene O6‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B1‐DNA adducts and p53 mutation in hepatocellular carcinoma

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O 6 - methylguanine-DNA methyltransferase

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O⁶-Methylguanine-DNA methyltransferase activity in human liver tumors

Inactivation of the DNA repair gene O⁶‐methylguanine‐DNA methyltransferase by promoter hypermethylation and its relationship to aflatoxin B₁‐DNA adducts and p53 mutation in hepatocellular carcinoma

Spontaneous hepatocellular carcinoma is reduced in transgenic mice overexpressing human O ⁶ - methylguanine-DNA methyltransferase