Deficient expression ofO 6-Methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma

Kohya, Naohiko; Miyazaki, Kohji; Matsukura, Shiroh; Yakushiji, Hiroyuki; Kitajima, Yoshihiko; Kono, Kenji; Fukuhara, Masao; Nakabeppu, Yusaku; Sekiguchi, Mutsuo

doi:10.1007/bf02573872

Cited by 31 publications

(41 citation statements)

References 37 publications

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“…Tumors with nodal metastasis (N1-2) in the present study showed more frequent loss of MGMT expression than those without nodal metastasis (N0). The association of MGMT loss with nodal metastasis has also been reported in other human cancers, such as oral, bile duct, and gastric cancers (17,18). Previous reports underscored its potential as a candidate of predictive marker for nodal metastasis.…”

Section: Discussionmentioning

confidence: 71%

Role of Loss of O⁶-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression

Myong

2010

Cancer Res Treat

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Section: Discussionmentioning

confidence: 71%

Role of Loss of O⁶-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression

Myong

2010

Cancer Res Treat

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“…In CC, MGMT expression has been found to be a good prognostic indicator on univariate analysis (133). In a further study, methylation of the MGMT promoter (which closely correlated with decreased protein expression) was significantly associated with poor survival (134).…”

Section: Genetic Repairmentioning

confidence: 83%

Prognostic molecular markers in cholangiocarcinoma: A systematic review

Briggs

Neal

Mann

et al. 2009

European Journal of Cancer

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The worldwide incidence of cholangiocarcinoma (CC) is steadily rising, the United Kingdom incidence now exceeding 1000 cases per year. It is an aggresive malignancy typified by unresponsiveness to existing chemotherapy and radiotherapy regimes in the vast majority of cases. Surgery offers the only hope of a cure, though postoperative disease recurrence is common, with 5-year survival rates following resection of less then 25%. Developments in molecular techniques and improved understanding of the basis of carcinogenesis in CC has led to examination of the role of biomarkers in predicting poor outcome. This systematic review examines published evidence relating to the prognostic significance of these molecular markers in CC. Of the molecular markers which have been investigated to date p53 mutation, cyclins, proliferation indices, mucins, CA19-9, CRP, and aneuploidy appear to hold significant potential as predictors of outcome in CC. These and other biomarkers may themselves represent novel therapeutic targets for CC.

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“…On the other hand, loss of MGMT expression could also be a negative prognostic factor because of an increased susceptibility to acquiring other mutations (48 -50). Finally, it is important to keep in mind that hypermethylation can simultaneously occur in other genes with a CpG island in their promoter regions (51), making it more difficult to predict the final behavior of tumor cells.…”

Section: Discussionmentioning

confidence: 99%

Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Determined by Promoter Hypermethylation and Immunohistochemical Expression in Anaplastic Gliomas

Brell

Tortosa²,

Verger³

et al. 2005

Clinical Cancer Research

180

155

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Purpose: Anaplastic gliomas constitute a heterogeneous group of tumors with different therapeutic responses to adjuvant chemotherapy with alkylating agents. O 6 -Methylguanine-DNA methyltransferase (MGMT), a DNA repair protein, is one of the implicated factors in glioma chemoresistance.The prognostic value of MGMTremains controversial due in part to the fact that previous published studies included heterogeneous groups of patients with different tumor grades. The aim of this study was to evaluate the prognostic significance of MGMT in patients with anaplastic glioma. Experimental Design: Ninety-three patients with anaplastic glioma were analyzed for MGMT protein expression by immunohistochemistry. In addition, for those patients from whom a good yield of DNA was obtained (n = 40), MGMT promoter methylation profile was analyzed by methylation-specific PCR. MGMT prognostic significance was evaluated together with other well-known prognostic factors. Results: Fifty-one tumors (54.8%) showed nuclear staining of MGMT. There was a trend towards longer overall survival for those patients with negative MGMT immunostaining (hazard ratio,1.66; P = 0.066). In a secondary analysis including those patients who actually received chemotherapy (n = 72), the absence of MGMTexpression was independently associated with better survival (hazard ratio, 2.12; P = 0.027). MGMT promoter methylation was observed in 50% of the analyzed tumors. No statistical correlation between MGMT expression and MGMT promoter hypermethylation was observed. Conclusions: Unlike previous studies, we did not find a correlation between MGMT promoter methylation and survival. However, we observed a correlation between MGMT protein expression and survival in those patients who received chemotherapy thus suggesting that the absence of MGMTexpression is a positive predictive marker in patients with anaplastic glioma.Anaplastic gliomas (WHO grade 3) show a wide variability of clinical outcome. Despite optimal treatment, mainly consisting of gross total resection followed by radiotherapy and chemotherapy with alkylating agents (1), therapeutic response and survival times vary considerably. This fact suggests that a large number of factors, including patient, tumor, and treatment characteristics, may influence the outcome (2 -4).Alkylating agents cause cell death by forming cross-links between adjacent strands of DNA due to alkylation of the O 6 position of guanine. The cellular DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) inhibits the cross-linking of double-stranded DNA by removing alkylating lesions (5 -7). A direct relationship between MGMT activity and resistance to alkylating nitrosoureas and methylating agents (i.e., ionizing radiations) has been well documented in cell lines and xenografts derived from a variety of human tumors, including gliomas (8). Moreover, depletion of MGMT activity with the substrate analogue inhibitor O 6

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Deficient expression ofO 6-Methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma

Abstract: Combined MGMT and MMR is a possible prognostic marker that probably reflects an accumulation of genetic mutations.

Cited by 31 publications

References 37 publications

Role of Loss of O⁶-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression

Role of Loss of O⁶-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression

Prognostic molecular markers in cholangiocarcinoma: A systematic review

Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Determined by Promoter Hypermethylation and Immunohistochemical Expression in Anaplastic Gliomas

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Deficient expression ofO 6-Methylguanine-DNA methyltransferase combined with mismatch-repair proteins hMLH1 and hMSH2 is related to poor prognosis in human biliary tract carcinoma

Abstract: Combined MGMT and MMR is a possible prognostic marker that probably reflects an accumulation of genetic mutations.

Cited by 31 publications

References 37 publications

Role of Loss of O6-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression

Role of Loss of O6-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression

Prognostic molecular markers in cholangiocarcinoma: A systematic review

Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Determined by Promoter Hypermethylation and Immunohistochemical Expression in Anaplastic Gliomas

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Role of Loss of O⁶-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression

Role of Loss of O⁶-Methylguanine DNA Methyltransferase (MGMT) Expression in Non-Small Cell Lung Carcinomas (NSCLCs): with Reference to the Relationship with p53 Overexpression