MLH1 -93G&gt;A Promoter Polymorphism and the Risk of Microsatellite-Unstable Colorectal Cancer

Raptis, Stavroula; Mrkonjic, Miralem; Green, Roger C.; Pethe, Vaijayanti; Monga, Neerav; Chan, Yuen Man; Daftary, Darshana; Dicks, Elizabeth; Younghusband, Banfield; Parfrey, Patrick S.; Gallinger, Steven; McLaughlin, John; Knight, Julia A.; Bapat, Bharati

doi:10.1093/jnci/djk095

Cited by 115 publications

(131 citation statements)

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“…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 CRC in persons with a family history of this disease 11 and microsatellite unstable CRC. 11 …”

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confidence: 63%

“…The MLH1 293A variant has previously been associated with an increased risk of developing hyperplastic colonic polyps in smokers, 10 CRC in persons with a family history of this disease, 11 and microsatellite-unstable CRC. 11 Taken together with our findings, these data suggest that the MLH1 293A variant defines a low penetrance risk allele for MMR-deficient CRC. Moreover, our observations extend this model by suggesting an association between the 293A variant and CRC with loss of MLH1 protein specifically.…”

Section: Discussionmentioning

confidence: 99%

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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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confidence: 63%

Section: Discussionmentioning

confidence: 99%

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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“…5,33,38-42 We found no evidence for an association between the MLH1 promoter germline SNP c.-93G4A genotype and an increased risk of MLH1 methylation or microsatellite instability in a case-control study of this cohort, arguing against a cis-acting role for this SNP in conferring susceptibility to methylation. In previous studies in which a positive association was found between the G4A genotype and microsatellite instability, either familial cases were retained in the cohort or the study group comprised early-onset cases, [8][9][10][11] suggesting that the genotype may be linked to founder mutations that give rise to familial or early-onset cancer phenotypes in these populations. Although in one study of a large colorectal cancer cohort, the c.-93G4A genotype was shown to be associated with MLH1 methylation, the BRAF V600E mutation as well as CIMP þ among sporadic microsatellite unstable cancers, nevertheless a stronger association between the G4A genotype was demonstrated among the microsatellite unstable cases with a positive family history.…”

Section: Discussionmentioning

confidence: 99%

“…6 The c.-93G4A SNP (rs1800734) within the MLH1 promoter has been associated with an increased risk of microsatellite instability or MLH1 methylation in some colorectal and endometrial cancer populations, but not in others. [7][8][9][10] However, these associations have been disputed on the basis that linkage disequilibrium with pathogenic mutations could not be ruled out in populations with a high incidence of familial cancer. 11 Recently, promoter reporter assays showed that the A allele of this SNP conferred reduced transcriptional activity compared with the G allele, consistent with the notion that this allele might predispose to promoter methylation.…”

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confidence: 99%

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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“…There are 20 case-control studies concerning -93G>A polymorphism (Ito et al, 1999;Deng et al, 2003;Park et al, 2004;Chen et al, 2005;Lee et al, 2005;Beiner et al, 2006;Song et al, 2006;Raptis et al, 2007;An et al, 2008;Harley et al, 2008;Koessler et al, 2008;Scott et al, 2008;Tulupova et al, 2008;Campbell et al, 2009;Shi et al, 2010;Shih et al, 2010;van Roon et al, 2010;Lacey et al, 2011;Lo et al, 2011;Whiffin et al, 2011) and 18 studies for I219V (Mathonnet et al, 2003;Listgarten et al, 2004;Lee et al, 2005;Mei et al, 2006;Song et al, 2006;Raptis et al, 2007;An et al, 2008;Capella et al, 2008;Smith et al, 2008;Campbell et al, 2009;Conde et al, 2009;Joshi et al, 2009;Nejda et al, 2009;Tanaka et al, 2009;Langeberg et al, 2010;Picelli et al, 2010 polymorphisms are summarized in Table 1. Most studies indicated that the genotypes distribution in the controls was consistent with Hardy-Weinberg equilibrium except for six studies for -93G>A (Park et al, 2004;Beiner et al, 2006;An...…”

Section: Characteristics Of Studiesmentioning

confidence: 99%

MLH1 Polymorphisms and Cancer risk: a Meta-analysis Based on 33 Case-control Studies

Yin²,

Huang³

et al. 2012

Asian Pacific Journal of Cancer Prevention

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MLH1 -93G>A Promoter Polymorphism and the Risk of Microsatellite-Unstable Colorectal Cancer

Abstract: In two patient populations, the MLH1 -93G>A polymorphism was associated with an increased risk of MSI-H colorectal cancer.

Cited by 115 publications

References 53 publications

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

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

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

MLH1 Polymorphisms and Cancer risk: a Meta-analysis Based on 33 Case-control Studies

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