MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer

Ogino, Shuji; Hazra, Aditi; Tranah, Gregory J.; Kirkner, Gregory J.; Kawasaki, Takako; Nosho, Katsuhiko; Ohnishi, Mutsuko; Suemoto, Yuko; Meyerhardt, Jeffrey A.; Hunter, David J.; Fuchs, Charles S.

doi:10.1093/carcin/bgm160

Cited by 86 publications

(81 citation statements)

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“…This is in contrast to the c.-56C4T SNP (rs16906252) of the DNA repair gene MGMT, which correlates strongly with the presence of MGMT promoter methylation in both colorectal carcinoma and non-neoplastic tissues, illustrating that cis-acting elements can have an instrumental role in gene methylation. [43][44][45] The lack of any association between MLH1 methylation and the c.-93G4A genetic variant in our cohort is consistent with the finding, instead, of a strong correlation between methylation of MLH1 and neighbouring genes within the contiguous 3p22 chromosomal region, arguing for a fundamental epigenetic basis to MLH1 inactivation in sporadic microsatellite unstable tumours.…”

Section: Discussionsupporting

confidence: 90%

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

et al. 2011

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Epigenetic silencing of cancer-related genes by promoter methylation is a frequent event in sporadic colorectal cancer. The CpG island methylator phenotype (CIMP þ ), in which discrete genes throughout the genome are simultaneously methylated, and long-range epigenetic silencing, whereby multiple genes within contiguous chromosomal regions are methylated, have been described in subsets of colorectal cancer. We previously reported the concurrent methylation of the mismatch repair gene MLH1 with a cluster of flanking genes in chromosome region 3p22 in sporadic colorectal carcinoma exhibiting microsatellite instability and the BRAF V600E mutation. Herein, we aimed to determine whether methylation of MLH1 and neighbouring 3p22 genes, singly or concomitantly, correlate with the germline c.-93G4A SNP within the MLH1 promoter, CIMP þ and other clinicopathological and molecular features of the tumours. By studying a cohort of 946 sporadic colorectal cancer cases, we show a strong association between concordant methylation of Z3 of five 3p22 genes with CIMP þ and the BRAF V600E mutation (Po0.001). These associations were independent of microsatellite instability, as concomitant methylation of 3p22 genes other than MLH1 was found in microsatellite stable cancers. These findings show that long-range epigenetic silencing across 3p22 occurs in the context of CIMP þ and the BRAF V600E mutation, and only gives rise to microsatellite instability when this process encompasses MLH1. Furthermore, the strong relationship between long-range epigenetic silencing of 3p22 and CIMP þ provides further evidence that these two purportedly distinct epigenetic phenotypes represent a single entity with a common aetiology. Low-level methylation of MLH1 and flanking 3p22 genes, as well as the BRAF V600E mutation, were detected in the apparently normal colonic mucosa of a small number of cases whose tumours showed a similar molecular profile, suggesting that these concurring genetic and epigenetic events can occur as a field defect in neoplastic development.

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Section: Discussionsupporting

confidence: 90%

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

et al. 2011

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“…22 There is also evidence that promoter methylation and transcriptional silencing of other loci occurs in an allele-specific manner during the pathogenesis of colorectal cancer. 23 However, we cannot exclude the possibility that the MLH1 293G>A polymorphism is in linkage disequilibrium with a highly penetrant germline MLH1 mutation for CRC, although the available evidence would argue against this. 24 We have recently demonstrated an association between the MLH1 293A variant and an elevated risk of therapy-induced acute-myeloid leukaemia (t-AML).…”

Section: Discussionmentioning

confidence: 90%

MLH1 −93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer

Allan

Shorto

Adlard

et al. 2008

Intl Journal of Cancer

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Rare inherited mutations in the mutL homolog 1 (MLH1) DNA mismatch repair gene can confer an increased susceptibility to colorectal cancer (CRC) with high penetrance where disease frequently develops in the proximal colon. The core promoter of MLH1 contains a common single nucleotide polymorphism (SNP) (293G>A, dbSNP ID:rs1800734) located in a region essential for maximum transcriptional activity. We used logistic regression analysis to examine the association between this variant and risk of CRC in patients in the United Kingdom. All statistical tests were 2 sided. In an analysis of 1,518 patients with CRC, homozygosity for the MLH1 293A variant was associated with a significantly increased 3-fold risk of CRC negative for MLH1 protein by immunohistochemistry (odds ratio (OR): AA vs GG 5 3.30, 95% CI 1.46-7.47, n 5 1392, p 5 0.004, MLH1 negative vs MLH1 positive CRC) and with a 68% excess of proximal CRC (OR: AA vs GG51.68, 95% confidence interval (CI) 1.00-2.83, n 5 1,518, p 5 0.05, proximal vs distal CRC). These findings suggest that the MLH1 293G>A polymorphism defines a low penetrance risk allele for CRC. ' 2008 Wiley-Liss, Inc.Key words: MLH1; mismatch repair; colorectal; polymorphism; proximal; promoter; dna repair; cancer MLH1 and MSH2 are components of the DNA mismatch repair (MMR) system, which recognises and repairs mismatches in DNA that occur during replication. 1 Rare constitutional mutations in MLH1, MSH2 and other genes are responsible for the autosomal dominant disorder hereditary nonpolyposis colorectal cancer (HNPCC), 2,3 where loss of MMR predisposes to colorectal cancer (CRC) with high penetrance. Loss of MMR can also develop somatically and occurs in 15-20% of all CRC. 4 Loss of MMR frequently involves MLH1 gene promoter silencing and concomitant loss of protein expression, which gives rise to CRC predominantly in the proximal colon. In addition to rare constitutional mutations, MMR genes also contain common single nucleotide polymorphisms (SNP) which can predispose to nonfamilial CRC with low to moderate penetrance, 5-7 suggesting an important contribution of common genetic variants to the burden of CRC in the general population.In view of the importance of MLH1 in colorectal carcinogenesis, we examined the association between a potentially functional SNP in MLH1 (dbSNP ID:rs1800734) and risk of CRC. The MLH1 293G>A polymorphism is located in the core promoter of MLH1, 93 bases upstream of the transcription start site in a region that is required for maximal transcriptional activity. 8,9 Polymorphic variation in this region is predicted to affect MLH1 protein expression. Indeed, site-directed mutagenesis of the adenine residue 2 bases downstream of the 293G>A polmorphism (position-91) reduces promoter activity by 75%. 9 These observations suggest that the MLH1 293G>A polymorphism might affect risk of CRC. Consistent with this hypothesis, the MLH1 293A variant has been associated with an increased risk of developing hyperplastic colonic polyps in smokers, 10

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“…Our reasons for doing this were two fold. First, it had been shown that there was a strong relationship between the T allele of this SNP in the MGMT 5′ UTR and the methylation of this gene in the tumors of patients with colorectal cancer (11). Second, Shen et al (10) had reported that 80% of colorectal cancer patients that had MGMT methylation in their tumors also had MGMT methylation in colonic mucosa >10 cm away from the tumor.…”

Section: Discussionmentioning

confidence: 99%

“…Ogino et al (11) investigated whether single nucleotide polymorphisms (SNP) in the MGMT gene had an effect on methylation of MGMT in colorectal cancers. The T allele of a SNP within the 5′ untranslated region (UTR; rs16906252; c.-56 C>T) was strongly associated with promoter methylation.…”

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confidence: 99%

Detection of MGMT Promoter Methylation in Normal Individuals Is Strongly Associated with the T Allele of the rs16906252 MGMT Promoter Single Nucleotide Polymorphism

Candiloro

Dobrovic

2009

Cancer Prevention Research

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Methylation of the CpG island in the MGMT promoter region is a frequent event in several cancer types including colorectal cancer, lung cancer, lymphoma, and glioblastoma. A correlation between methylation and the T allele of the rs16906252 single nucleotide polymorphism (SNP) in colorectal carcinomas has previously been reported. As aberrant MGMT methylation can be an early event in tumor development, we tested the hypothesis that normal individuals possessing the T allele may be predisposed to somatic methylation at the MGMT promoter. Peripheral blood monononuclear cell DNA from 89 normal, healthy individuals was genotyped at rs1690625 and assessed for the methylation status of the MGMT promoter region using independent quantitative methodologies capable of detecting lowlevel methylation: MethyLight and Sensitive Melting Analysis after Real-time MethylationSpecific PCR (SMART-MSP). There was a strong association between presence of the T allele and detectable methylation (P = 0.00005) in the peripheral blood DNA. Furthermore, when a MSP assay flanking the SNP was used to amplify methylated sequences in heterozygotes, only the T allele was methylated. Thus, detectable somatic methylation of the MGMT promoter in normal individuals is strongly associated with the T allele of the rs16906252 MGMT promoter SNP.Inactivation of tumor suppressor genes and DNA stability genes by promoter methylation is a common occurrence in human cancer. In some cases, epigenetic inactivation of one of these genes is likely to be the initiating event in cancer development (reviewed in ref. 1). Evidence for this is particularly strong for certain hereditary cancer genes where constitutional methylation of the gene predisposes to cancer development (2-4).It is also likely that constitutional methylation of other genes not normally involved in heritable cancer can predispose to cancer. One of the most plausible candidates for a gene whose inactivation may initiate carcinogenesis is MGMT, which codes for a protein that removes alkyl adducts from the O6 position of guanine (5). Loss of MGMT function will give rise to a mutator phenotype, as alkylation damage from a variety of environmental sources is a common occurrence and as alkylated guanine is likely to mispair with thymine during DNA replication. MGMT methylation is commonly found in various cancers including colorectal cancers, gliomas, head and neck cancers, and lymphomas (6). MGMT promoter methylation has been used as a predictive marker in cancers; it indicates those individuals who are likely to respond to chemotherapy with alkylating agents (7,8).MGMT methylation may be an early or even predisposing event in colorectal cancer. Esteller et al. (9) reported that MGMT methylation was present in adenomas. Shen et al. (10) reported that MGMT methylation was found in apparently normal colonic tissue up to 10 cm from an MGMT-methylated colorectal cancer indicating that MGMT methylation can even be observed prior to any detectable change in morphology.Ogino et al. (11) investi...

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MGMT germline polymorphism is associated with somatic MGMT promoter methylation and gene silencing in colorectal cancer

Cited by 86 publications

References 37 publications

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

Methylation of the 3p22 region encompassing MLH1 is representative of the CpG island methylator phenotype in colorectal cancer

MLH1 −93G>A promoter polymorphism and risk of mismatch repair deficient colorectal cancer

Detection of MGMT Promoter Methylation in Normal Individuals Is Strongly Associated with the T Allele of the rs16906252 MGMT Promoter Single Nucleotide Polymorphism

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