Hypermethylation of the DNA Repair Gene O6-Methylguanine DNA Methyltransferase and Survival of Patients With Diffuse Large B-Cell Lymphoma

Esteller, Manel; Gaïdano, Gianluca; Goodman, Steven N.; Zagonel, Vittorina; Capello, Daniela; Botto, Barbara; Rossi, Davide; Gloghini, Annunziata; Vitolo, Umberto; Carbone, Antonino; Baylin, Stephen B.; Herman, James G.

doi:10.1093/jnci/94.1.26

Cited by 289 publications

(197 citation statements)

References 17 publications

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“…Loss of MGMT expression is rarely due to deletion, rearrangement or mutation of the MGMT gene, and approximately 20% of human tumour cell lines lack MGMT activity, suggesting that the gene is under epigenetic control. 21,22 Silencing of the MGMT gene has been reported in diffuse large B-cell lymphoma (36%) 40 and in immunodeficiency-related NHL with a similar frequency. 41 In addition, the pathogenetic role of MGMT inactivation is supported by the fact that MGMT knockout mice develop lymphoma with high frequency, 42 this inactivation being an important mechanism in lymphomagenesis.…”

Section: Discussionmentioning

confidence: 95%

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

et al. 2006

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Monoclonal gammopathies are a group of disorders characterized by clonal proliferation and accumulation of immunoglobulin-producing plasma cells. Multiple myeloma and monoclonal gammopathy of undetermined significance are the most common monoclonal gammopathies; the two comprise a spectrum of disorders, ranging from a relatively benign disease, monoclonal gammopathy of undetermined significance, to a malignant disease, multiple myeloma. Aberrant promoter methylation represents a primary mechanism of gene silencing during tumorigenesis. DNA repair systems act to maintain genome integrity in the presence of replication errors, environmental insults, and the cumulative effects of aging. The methylation patterns of two genes implicated in DNA repair, O6 methylguanine DNA methyl-transferase (MGMT) and human mutL homologue1 (hMLH1) have been detected in various solid tumours. With the purpose of studying the gene silencing of MGMT and hMLH1 in plasma cell disorders, we investigated the methylation status and expression of both genes in: 29 cases of multiple myeloma; one case of plasma cell leukaemia; 13 cases of monoclonal gammopathy of undetermined significance; and two cases of polyclonal plasmacytosis, using methylationspecific polymerase-chain reaction and immunohistochemical techniques. Methylation frequencies for MGMT were 23% in multiple myeloma and 8% in monoclonal gammopathy of undetermined significance. It was 10% for hMLH1 in multiple myeloma. None of the patients diagnosed with monoclonal gammopathy of undetermined significance had hMLH1 hypermethylated. In addition, 50% of myeloma cases had a loss of hMLH1 expression, whereas silencing of MGMT was observed in 43% of myeloma and 36% of samples with monoclonal gammopathy of undetermined significance. This study indicates that repair pathway defects play a role in the pathogenesis and evolution of monoclonal gammopathies, and suggests that inactivation of hMLH1 could be implicated in multiple myeloma tumorigenesis.

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Section: Discussionmentioning

confidence: 95%

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

et al. 2006

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“…Epigenetic silencing of tumor suppressor genes is at least as common as mutation as a mechanism of gene inactivation. A broad spectrum of genes belonging to different classes of activity such as DNA repair (Esteller et al, 2002), cell cycle control (Xing et al, 2004), signal transduction (Terasawa et al, 2004), angiogenesis (Yang et al, 2003) and invasion (Seidl et al, 2004) are inactivated by DNA methylation in cancer cells. The second layer of epigenetic transcriptional control is histone modification such as acetylation, methylation, phosphorylation and ubiquitination (LaVoie, 2005).…”

Section: Introductionmentioning

confidence: 99%

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

et al. 2007

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To investigate the mechanism by which HSulf-1 expression is downregulated in ovarian cancer, DNA methylation and histone acetylation of HSulf-1 was analysed in ovarian cancer cell lines and primary tumors. Treatment of OV207 and SKOV3 by 5-aza-2 0 -deoxycytidine resulted in increased transcription of HSulf-1. Sequence analysis of bisulfite-modified genomic DNA from ovarian cell lines and primary tumors without HSulf-1 expression revealed an increase in the frequency of methylation of 12 CpG sites in exon 1A. Chromatin immunoprecipitation assays showed an increase in histone H3 methylation in cell lines without HSulf-1 expression. To assess the significance of HSulf-1 downregulation in ovarian cancer, OV167 and OV202 cells were transfected with HSulf-1 siRNA. Downregulation of HSulf-1 expression in OV167 and OV202 cells lead to an attenuation of cisplatin-induced cytotoxicity. Moreover, patients with ovarian tumors expressing higher levels of HSulf-1 showed a 90% response rate (27/30) to chemotherapy compared to a response rate of 63% (19/30) in those with weak or moderate levels (P ¼ 0.0146, v 2 test). Collectively, these data indicate that HSulf-1 is epigenetically silenced in ovarian cancer and that epigenetic therapy targeting HSulf-1 might sensitize ovarian tumors to conventional first-line therapies.

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“…DNA hypermethylation often correlates with inappropriate gene silencing and is well documented in primary human lymphomas and cell lines (Rush and Plass, 2002;Esteller, 2003b;Galm et al, 2006), and includes genes whose hypermethylation distinguish specific hematologic malignancies (Herman et al, 1997) or clinical outcome (Esteller et al, 2002). To date, altered DNA methylation in lymphoma has largely been addressed by direct candidate gene approaches.…”

Section: Introductionmentioning

confidence: 99%

Global DNA methylation profiling reveals silencing of a secreted form of Epha7 in mouse and human germinal center B-cell lymphomas

et al. 2007

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Most human lymphomas originate from transformed germinal center (GC) B lymphocytes. While activating mutations and translocations of MYC, BCL2 and BCL6 promote specific GC lymphoma subtypes, other genetic and epigenetic modifications that contribute to malignant progression in the GC remain poorly defined. Recently, aberrant expression of the TCL1 proto-oncogene was identified in major GC lymphoma subtypes. TCL1 transgenic mice offer unique models of both aggressive GC and marginal zone B-cell lymphomas, further supporting a role for TCL1 in B-cell transformation. Here, restriction landmark genomic scanning was employed to discover tumor-associated epigenetic alterations in malignant GC and marginal zone B-cells in TCL1 transgenic mice. Multiple genes were identified that underwent DNA hypermethylation and decreased expression in TCL1 transgenic tumors. Further, we identified a secreted isoform of EPHA7, a member of the Eph family of receptor tyrosine kinases that are able to influence tumor invasiveness, metastasis and neovascularization. EPHA7 was hypermethylated and repressed in both mouse and human GC B-cell non-Hodgkin lymphomas, with the potential to influence tumor progression and spread. These data provide the first set of hypermethylated genes with the potential to complement TCL1-mediated GC B-cell transformation and spread.

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Hypermethylation of the DNA Repair Gene O6-Methylguanine DNA Methyltransferase and Survival of Patients With Diffuse Large B-Cell Lymphoma

Abstract: MGMT promoter hypermethylation appears to be a useful marker for predicting survival in patients with B-DLCL treated with multidrug regimens including cyclophosphamide.

Cited by 289 publications

References 17 publications

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

hMLH1 and MGMT inactivation as a mechanism of tumorigenesis in monoclonal gammopathies

Epigenetic silencing of HSulf-1 in ovarian cancer:implications in chemoresistance

Global DNA methylation profiling reveals silencing of a secreted form of Epha7 in mouse and human germinal center B-cell lymphomas

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