Microsatellite Instability in Cancer of the Proximal Colon

Thibodeau, Stephen N.; Bren, Gary D.; Schaid, Daniel J.

doi:10.1126/science.8484122

Cited by 2,737 publications

(1,769 citation statements)

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“…MSI serves as a useful marker of the mutator phenotype that is characteristic of HNPCC and has been attributed to mutations in one of several MMR genes including hMSH2, hMLH1, hPMS1 and hPMS2 Bronner et al, 1994;Fishel et al, 1994;Nicolaides et al, 1994;Papadopoulos et al, 1994). MSI has been described in a variety of sporadic cancers, such as colon (Thibodeau et al, 1993), endometrium (Risinger et al, 1993) pancreas and stomach (Han et al, 1993) and prostate (Uchida et al, 1996). Previous studies have also reported a high frequency of MSI in bladder cancer Steiner et al, 1997;Mourah et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

et al. 2001

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Mutation of human homologues of DNA mismatch repair (MMR) genes in tumours has been shown to be associated with the phenomenon of microsatellite instability (MSI). Several studies have reported the occurrence of MSI in bladder cancer, but evidence of involvement of MMR genes in the pathogenesis of this cancer is still unclear. We therefore utilized quantitative immunohistochemical (IHC) image analysis and PCR-based allelotype analysis to determine hMLH1 and hMSH2 genes alteration in a cohort of Egyptian bladder cancer samples. IHC analysis of 24 TCC and 12 SCC revealed marked- intra and intertumour heterogeneity in the levels of expression of the two MMR proteins. One TCC lost MLH1 expression and one lost MSH2, (1/24, 4%), and one SCC lost MSH2 (1/12, 8%). A large proportion of analysed tumours revealed a percentage positivity of less than 50% for MLH1 and MSH2 expression (44% and 69%, respectively). Complete loss of heterozygosity in three dinucleotide repeats lying within, or in close proximity to, hMLH1 and hMSH2 was rare (2/57, (4%) for MLH1 ; and 1/55, (2%) for MSH2 ), however allelic imbalance was detected in 11/57 ( hMLH1 ) and 10/55 ( hMSH2 ) at any of the informative microsatellite loci. These alterations in structure and expression of DNA MMR genes suggest their possible involvement in the tumorigenesis and/or progression of bladder cancer. © 2001 Cancer Research Campaign http://www.bjcancer.com

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Section: Discussionmentioning

confidence: 99%

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

et al. 2001

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“…1 A classic example of this is the biallelic promoter methylation of the mismatch repair gene, MLH1, which accounts for B70% of sporadic colorectal cancers that exhibit microsatellite instability as a direct consequence of impaired mismatch repair activity. [2][3][4][5] MLH1 methylation occurs in close association with the presence of the oncogenic BRAF V600E mutation in sporadic colorectal cancer. 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.…”

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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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“…They accumulate frequent deletions and insertions in microsatellite DNA sequences due to de®cient repair of spontaneous errors which occur during the replication of these repetitive DNA sequences Thibodeau et al, 1993;Ionov et al, 1993). The MSI-H phenotype is associated with the hereditary nonpolyposis colorectal cancer (HNPCC) syndrome as a result of predisposing constitutional mutations in genes involved in DNA mismatch repair (Bronner et al, 1994;Papadopoulos et al, 1994;Fishel et al, 1993;Leach et al, 1993).…”

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Variable mutation frequencies in coding repeats of TCF-4 and other target genes in colon, gastric and endometrial carcinoma showing microsatellite instability

et al. 1999

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Microsatellite Instability in Cancer of the Proximal Colon

Cited by 2,737 publications

References 28 publications

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

Immunohistochemical analysis of expression and allelotype of mismatch repair genes (hMLH1 and hMSH2) in bladder cancer

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

Variable mutation frequencies in coding repeats of TCF-4 and other target genes in colon, gastric and endometrial carcinoma showing microsatellite instability

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