Mismatch Repair Defects andO 6-Methylguanine-DNA Methyltransferase Expression in Acquired Resistance to Methylating Agents in Human Cells

Hampson, Richard; Humbert, Odile; Macpherson, Peter; Aquilina, Gabriele; Karran, Peter

doi:10.1074/jbc.272.45.28596

Cited by 55 publications

(27 citation statements)

References 36 publications

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“…This may suggest that these lesions are deficient in mismatch repair, but have not yet accumulated a large number of microsatellite alterations and do not yet have an apparent MSIϩ phenotype. Data that may support this explanation are the presence of cancer cell lines defective in mismatch repair not showing MSI 47 and the presence of hMLH1 promoter hypermethylation in gastric carcinomas showing only a low rate of MSI. 36 In our series, an example of progression through this pathway would be a case in which we observed hMLH1 methylation and MSI in the UEC, but the AEH contiguous to this cancer does not shown an apparent MSI phenotype, although it is methylated at hMLH1.…”

Section: Discussionmentioning

confidence: 58%

hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis

Esteller¹,

Catasús

Matías‐Guiu

et al. 1999

The American Journal of Pathology

281

177

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It has recently been suggested that silencing of the hMLH1 gene by promoter hypermethylation is the mechanism underlying the presence of the microsatellite instability (MSI) phenotype in sporadic colon and endometrial carcinomas. To determine whether hMLH1 promoter hypermethylation is a relatively early event in endometrial tumorigenesis we evaluated endometrial hyperplasia (EH) characterized as simple , complex , and atypical (the direct precursor of endometrial carcinoma) for hMLH1 aberrant methylation. In addition , we studied the hMLH1 , hMSH2, hMSH3, and hMSH6 promoter methylation and MSI status of those endometrial carcinomas with synchronous hyperplasias and those without them. We found that 11 of 12 (91%) cases of endometrial carcinoma (EC) displaying MSI had hMLH1 promoter hypermethylation , whereas aberrant methylation of any of the other mismatch repair genes was not observed. All 15 cases of EC without MSI were unmethylated at hMLH1. Abnormal methylation of hMLH1 was also present in 8 of 116 (7%) cases of EH and was restricted primarily to the atypical endometrial hyperplasia (AEH) type with coexisting endometrial carcinoma. In this set , half of EH methylated at hMLH1 displayed MSI , whereas none of the unmethylated EH had MSI. Our data suggest that hypermethylation of hMLH1 can be an early event in the pathogenesis of EC, preceding the development of an apparent MSI phenotype in a subset of cases. (Am J Pathol 1999, 155:1767-1772)Endometrial carcinoma is the most common gynecological malignancy and is the fourth most common cancer of women in the United States.1 Uterine endometrioid carcinoma (UEC) is the most common histological type. UEC often precedes or coexists with endometrial hyperplasias, which have been proposed as possible precursor lesions.2,3 Atypical endometrial hyperplasia (AEH) is most associated with progression to carcinoma, and women with AEH without concurrent invasive carcinoma have a 30% risk of developing UEC.3 UEC and AEH share cytological atypia and a monoclonal pattern, 4,5 but UEC are distinguished by the presence of invasion.3 A spectrum of hyperplasia without atypia, including simple and complex hyperplasia, also exists. These lesions show a low rate of progression to UEC 3 and a putative polyclonal pattern. 4,5Very little is known about the genetic alterations underlying the biology of the precursor lesions of UEC. Only mutations in the oncogene K-ras and the tumor suppressor gene PTEN have been described in AEH.6,7 PTEN mutations may even precede the appearance of an evident atypia in the endometrial hyperplasia.8 However, a subset of AEH displays the microsatellite instability (MSI) phenotype.5,7,9,10 MSI was first detected in tumors from patients with hereditary non-polyposis colorectal carcinoma (HNPCC). In this setting, the cause of MSI has been attributed to germline defects in DNA mismatch repair (MMR) genes, mainly involving hMLH1 and hMSH2. 11-19Other MMR genes identified include hPMS1, hPMS2, hMSH3, and hMSH6. 20 -21 Endometrial carcinoma (EC) is the most com...

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Section: Discussionmentioning

confidence: 58%

hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis

Esteller¹,

Catasús

Matías‐Guiu

et al. 1999

The American Journal of Pathology

281

177

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“…It rather becomes converted into a critical downstream lesion that is supposed to be DSBs. This occurs, according to a reasonable model, by mispairing of O 6 MeG lesions with thymine, which in turn is processed by MutSa-dependant mismatch repair provoking a futile MMR cycle (Karran and Bignami, 1994;Hampson et al, 1997). Secondary lesions will be formed that cause replication interference in the subsequent DNA replication cycle leading ultimately to DSBs (Ochs and Kaina, 2000).…”

Section: Discussionmentioning

confidence: 99%

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

Roos¹,

et al. 2006

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Methylating drugs such as temozolomide (TMZ) are widely used in the treatment of brain tumours (malignant gliomas). The mechanism of TMZ-induced glioma cell death is unknown. Here, we show that malignant glioma cells undergo apoptosis following treatment with the methylating agents N-methyl-N 0 -nitro-N-nitrosoguanidine (MNNG) and TMZ. Cell death determined by colony formation and apoptosis following methylation is greatly stimulated by p53. Transfection experiments with O 6 -methylguanine-DNA methyltransferase (MGMT) and depletion of MGMT by O 6 -benzylguanine showed that, in gliomas, the apoptotic signal originates from O 6 -methylguanine (O 6 MeG) and that repair of O 6 MeG by MGMT prevents apoptosis. We further demonstrate that O 6 MeGtriggered apoptosis requires Fas/CD95/Apo-1 receptor activation in p53 non-mutated glioma cells, whereas in p53 mutated gliomas the same DNA lesion triggers the mitochondrial apoptotic pathway. This occurs less effectively via Bcl-2 degradation and caspase-9, -2, -7 and -3 activation. O 6 MeG-triggered apoptosis in gliomas is a late response (occurring >120 h after treatment) that requires extensive cell proliferation. Stimulation of cell cycle progression by the Pasteurella multocida toxin promoted apoptosis whereas serum starvation attenuated it. O 6 MeGinduced apoptosis in glioma cells was preceded by the formation of DNA double-strand breaks (DSBs), as measured by cH2AX formation. Glioma cells mutated in DNA-PK cs , which is involved in non-homologous endjoining, were more sensitive to TMZ-induced apoptosis, supporting the involvement of DSBs as a downstream apoptosis triggering lesion. Overall, the data demonstrate that cell death induced by TMZ in gliomas is due to apoptosis and that determinants of sensitivity of gliomas to TMZ are MGMT, p53, proliferation rate and DSB repair.

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“…The immediate-early translocation of MMR proteins into the nucleus, triggered very likely by O 6 -MeG/C and O 6 -MeG/T lesions, is supposed to provoke an increase in MMR capacity in the nucleus; this would be important, in view of O6-MeG/C lesions that form during replication highly mutagenic GT mismatches. Defects in MMR are associated with various hereditary forms of cancer (2, 18, 49); they have also been shown to increase dramatically the resistance of cells to O 6 -MeG-generating agents, notably if MGMT is not expressed or is expressed at a low level (7,8,14,29,50). MMR defects, therefore, have a strong impact on the mutagenic and carcinogenic response of cells exposed to alkylating agents.…”

Section: Discussionmentioning

confidence: 99%

“…These agents, such as N-methyl-NЈ-nitro-N-nitrosoguanidine (MNNG) 1 and N-methyl-N-nitrosourea (MNU), cause methylation in the O 6 position of guanine. The resulting O 6 -methylguanine (O 6 -MeG) pairs with thymine instead of cytosine, thus leading to GC 3 AT transition mutations (7)(8)(9). O 6 -MeG paired with thymine, as well as various other mutagen-induced lesions such as 1,2-intrastrand d(GpG) cross-links generated by cisplatin, are subject of repair by the mismatch repair system (10,11).…”

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confidence: 99%

Nuclear Translocation of Mismatch Repair Proteins MSH2 and MSH6 as a Response of Cells to Alkylating Agents

Christmann¹,

Kaina²

2000

Journal of Biological Chemistry

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Mismatch Repair Defects andO 6-Methylguanine-DNA Methyltransferase Expression in Acquired Resistance to Methylating Agents in Human Cells

Cited by 55 publications

References 36 publications

hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis

hMLH1 Promoter Hypermethylation Is an Early Event in Human Endometrial Tumorigenesis

Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine

Nuclear Translocation of Mismatch Repair Proteins MSH2 and MSH6 as a Response of Cells to Alkylating Agents

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