Mutation of a
            <i>mutL</i>
            Homolog in Hereditary Colon Cancer

Papadopoulos, Nickolas; Nicolaides, Nicholas C.; Wei, Yu-Ling; Ruben, Steven M.; Carter, Kenneth C.; Rosen, Craig A.; Haseltine, William A.; Fleischmann, Robert; Fraser, Claire M.; Adams, Mark D.; Venter, J. Craig; Hamilton, Stanley R.; Petersen, Gloria M.; Watson, Patrice; Lynch, Henry T.; Peltomäki, Païvi; Mecklin∥, Jukka–Pekka; Chapelle, Albert de la; Kinzler, Kenneth W.; Vogelstein, Bert

doi:10.1126/science.8128251

Cited by 1,707 publications

(743 citation statements)

References 28 publications

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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).…”

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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“…The role of genomic rearrangements in the etiology of HNPCC has been under-investigated, due to the lack of technically simple and reliable approaches for detecting this type of mutation. Recently, with the development of PCR-based semi-quantitative approaches for detecting gene dosage, it has become apparent that a substantial proportion of HNPCC cases are associated with germ-line genomic rearrangements in the MMR genes, mainly MLH1and MSH2 (Papadopoulos et al, 1994;Nystrom-Lahti et al, 1995;Mauillon et al, 1996;Wijnen et al, 1998;Charbonnier et al, 2000;Charbonnier et al, 2002;Gille et al, 2002;Viel et al, 2002;Wang et al, 2002;Nakagawa et al, 2003;Plaschke et al, 2003;Pyatt et al, 2003;Taylor et al, 2003;Wang et al, 2003;Di Fiore et al, 2004;Miyaki et al, 2004;Thiffault et al, 2004;Casey et al, 2005). A germ-line genomic deletion in HNPCC was first identified as a founder mutation at MLH1 among the Finnish population (Nystrom-Lahti et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

Distinct patterns of germ-line deletions inMLH1 andMSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC)

McVety

Younan

et al. 2006

Hum. Mutat.

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A relatively high frequency of germ-line genomic rearrangements in MLH1 and MSH2 has been reported among Lynch Syndrome (HNPCC) patients from different ethnic populations. To investigate the underlying molecular mechanisms, we characterized the DNA breakpoints of 11 germ-line deletions, six for MLH1 and five for MSH2. Distinct deletion patterns were found for the two genes. The five cases of MSH2 deletions result exclusively from intragenic unequal recombination mediated by repetitive Alu sequences. In contrast, five out of the six MLH1 deletions are due to recombinations involving sequences of no significant homology (P =0.015). A detailed analysis of the DNA breakpoints in the two genes, previously characterized by other groups, validated the observation that Alumediated unequal recombination is the main type of deletion in MSH2 (n = 34), but not in MLH1 (n = 21) (P <0.0001). Plotting the distribution of known DNA breakpoints among the introns of the two genes showed that, the highest breakpoint density is co-localized with the highest Alu density. Our study suggests that Alu is a promoting factor for the genomic recombinations in both MLH1 and MSH2, and the local Alu density may be involved in shaping the deletion pattern.

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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). The MSI-H phenotype is also observed in about 15% of sporadic colon, gastric and endometrial carcinomas.…”

mentioning

confidence: 99%

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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Mutation of a mutL Homolog in Hereditary Colon Cancer

Cited by 1,707 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

Distinct patterns of germ-line deletions inMLH1 andMSH2: the implication of Alu repetitive element in the genetic etiology of Lynch syndrome (HNPCC)

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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