Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer

Ce, Bronner; Sm, Baker; Pt, Morrison; Warren, Gwynedd; Ll, Smith; Mk, Lescoe; Kane, Michael F.; Earabino, C; Lipford, J. Russell; Lindblom, Annika

doi:10.1038/368258a0

Cited by 1,850 publications

(851 citation statements)

References 24 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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“…This model has been actually con®rmed by the ®nding that the hereditary nonpolyposis colorectal cancer (HNPCC) is associated with defects in genes coding for homologues of the bacterial mismatch repair proteins MutS or MutL (Fishel et al, 1993;Leach et al, 1993;Parsons et al, 1993;Jiricny, 1994; Edelman et al, 1997). Indeed, cells from these tumours have a hypermutator phenotype and the biochemical defect in the mismatch repair process was established (Bronner et al, 1994;Richards et al, 1997). If inactivation of the OGG1 gene in mammalian cells also causes a mutator phenotype, it can be expected that cells lacking the Ogg1 activity could have enhanced possibility to undergo cancer transformation.…”

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Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours

et al. 1998

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The human OGG1 gene encodes a DNA glycosylase activity catalysing the excision of the mutagenic lesion 7,8-dihydro-8-oxoguanine from oxidatively damaged DNA. The OGG1 gene was localized to chromosome 3p25, a region showing frequent loss of heterozygosity (LOH) in lung and kidney tumours. In this study, we have analysed by RT ± PCR the expression of OGG1 in 25 small cell lung cancers, in 15 kidney carcinomas and the 15 normal kidney counterparts. The results show that OGG1 messenger RNA can be detected in all tumours tested and that no signi®cant di erence was observed in the level of expression between normal and tumoral kidney tissues. Denaturing gradient gel electrophoresis (DGGE) was used to screen this series of human tumours for alterations in the OGG1 cDNA. The study revealed homozygous mutations in three tumours, two from lung and one from kidney. Sequencing analysis of the mutants identi®ed a single base substitution in each of the three cases: two tranversions (GC to TA and TA to AT) and one transition (GC to AT). All three substitutions cause an amino acid change in the hOgg1 protein. For the mutant kidney tumour, the normal tissue counterpart shows a wild-type pro®le. These results suggest a role for OGG1 mutations in the course of the multistage process of carcinogenesis in lung or kidney.Keywords: oxidative DNA damage; DNA repair; missense mutations of OGG1 gene; human lung and kidney cancer; tumour suppressor gene Damage to DNA by oxygen-free radicals is postulated to cause mutations that are associated with the initiation or the progression of human cancers (Breimer, 1990;Loeb, 1997;Beckman and Ames, 1997). Oxidative damage-induced mutations can activate oncogenes or inactivate tumour suppressor genes altering the cell growth control (Fearon, 1997). An oxidatively damaged guanine, 7,, is abundantly produced in DNA as a consequence of the cellular oxidative metabolism or the exposure to ionizing radiation or chemical carcinogens (Dizdaroglu, 1991;Cadet et al., 1997). The presence of 8-OxoG in DNA has been shown to be mutagenic since, while this lesion does not impede DNA chain elongation, it preferentially pairs with adenine during in vitro DNA synthesis (Shibutani et al., 1991). The biological incidence of the presence of 8-OxoG in DNA has been unveiled by the study of two genes in E. coli, fpg (mutM) and mutY (micA) which code for DNA glycosylases that cooperate to prevent the mutagenic e ects of 8-OxoG in DNA (Boiteux et al., 1987;Cabrera et al., 1988;Radicella et al., 1988;Nghiem et al., 1988;Au et al., 1989). Inactivation of either gene leads to a spontaneous mutator phenotype characterized by the exclusive increase in GC to TA transversions (Michaels and Miller, 1992;Grollman and Moriya, 1993;Boiteux and Laval, 1997). In Saccharomyces cerevisiae the OGG1 gene was cloned as the functional eukaryotic homologue of the bacterial fpg gene (Au ret van der Kemp et al., 1996). The yeast Ogg1 protein is a DNA glycosylase/AP lyase which excises 8-OxoG, formamidopyrimidines and incizes apurinic/apyrimid...

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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.…”

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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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Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancer

Cited by 1,850 publications

References 24 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

Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours

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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