A Naturally Occurring <i>hPMS2</i> Mutation Can Confer a Dominant Negative Mutator Phenotype

Nicolaides, Nicholas C.; Littman, Susan J.; Modrich, Paul; Kinzler, Kenneth W.; Vogelstein, Bert

doi:10.1128/mcb.18.3.1635

Cited by 87 publications

(91 citation statements)

References 30 publications

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“…We were unable to demonstrate an altered methylation of the promoter region of the hMLH1 gene in the colon sample showing only the somatic mutation of the gene. However, we could not exclude that the second allele is inactivated by other mechanisms, such as large deletion or that the found mutation could be dominant-negative like the truncating mutation at codon 134 of the hPMS2 mismatch repair gene (Nicolaides et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours

et al. 1999

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Summary Genomic instability has been proposed as a new mechanism of carcinogenesis involved in hereditary non-polyposis colorectal cancer (HNPCC) and in a large number of sporadic cancers like pancreatic and colon tumours. Mutations in human mismatch repair genes have been found in HNPCC patients, but their involvement in sporadic cancer has not been clarified yet. In this study we screened 21 pancreatic and 23 colorectal sporadic cancers for microsatellite instability by ten and six different microsatellite markers respectively. Microsatellite alterations were observed at one or more loci in 66.6% (14/21) of pancreatic cancers and in 26% (6/23) colon tumours, but all the pancreatic and half of the colon samples showed a low rate of microsatellite instability. All the unstable samples were further analysed for mutations in the hMLH1 and hMSH2 genes and for hypermethylation of the hMLH1 promoter region. Alterations in the hMLH1 gene were found only in colorectal tumours with a large presence of microsatellite instability. None of the pancreatic tumours showed any alteration in the two genes analysed. Our results demonstrate that microsatellite instability is unlikely to play a role in the tumorigenesis of sporadic pancreatic cancers and confirm the presence of mismatch repair gene alterations only in sporadic colon tumours with a highly unstable phenotype.

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Section: Discussionmentioning

confidence: 99%

Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours

et al. 1999

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“…MMR gene mutations are not always dominant by the pattern of transmission, as exemplified by PMS2 (De Rosa et al, 2000). On the cellular level, MMR gene mutations are not always recessive, but may have dominant-negative effects (Jager et al, 1997;Nicolaides et al, 1998), or be associated with haploinsufficiency (Cejka et al, 2003;Takagi et al, 2003). Furthermore, although initial studies suggested that all LOH events occurring in HNPCC tumors from MLH1 mutation carriers (6/6, 100%) affect the wt allele (Hemminki et al, 1994), a recent investigation found that up to 40% (8/20) of LOH present in HNPCC CRC may target the mutant allele (Sanchez de Abajo et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

et al. 2007

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Mutations in the DNA mismatch repair gene MLH1 are a major cause of hereditary nonpolyposis colorectal cancer (HNPCC). No mutant phenotype is observed before the wild-type (wt) allele is somatically inactivated in target tissue. We addressed the mechanisms of MLH1 inactivation in 25 colorectal (CRC) and 32 endometrial cancers (ECs) from MLH1 mutation carriers (Mut1, in-frame genomic deletion; Mut2, out-of-frame splice site mutation; Mut3, missense mutation). By a quantitative method, matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF), utilizing four intragenic single nucleotide polymorphisms and mutations, loss of heterozygosity (LOH) was present in 31/57 (54.4%) of tumors. The wt allele displayed LOH more often than the mutant allele (23/57 vs 8/57, P ¼ 0.006). For Mut1, LOH was more frequent in CRC than EC (10/11 vs 1/13, Po0.0001), whereas Mut2 and Mut3 displayed opposite LOH pattern. Moreover, although wt LOH predominated in CRC irrespective of the predisposing mutation, LOH often affected the mutant allele in EC from Mut2 and Mut3 carriers (6/19, 31.6%). MLH1 promoter methylation, which reflected a more widespread hypermethylation tendency, occurred in 4/55 (7.3%) of tumors and was inversely associated with LOH. In conclusion, the patterns of somatic events (LOH and promoter methylation) differ depending on the tissue and germline mutation, which may in part explain the differential tumor susceptibility of different organs in HNPCC. MALDI-TOF provides a novel approach for the detection and quantification of LOH.

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“…Five of these genes encode proteins involved in the DNA repair pathway (Prolla et al, 1994;Drummond et al, 1995). Except in rare cases (Nicolaides et al, 1998), the mechanism leading to deficiency in DNA mismatch repair (MMR) is recessive and involves 'two hits': HNPCC patients inherit a mutated allele, then a second somatic genetic or epigenetic event occurs on the wild-type allele during the development of the tumour (Hemminki et al, 1994;Konishi et al, 1996). Through the recognition and repair of incorrectly paired nucleotides, these cancer-susceptibility genes encode cellular Extensive molecular screening for hereditary non-polyposis colorectal cancer proteins whose function is essential to the integrity of the genome and therefore belong to the 'caretakers' category (Kinzler and Vogelstein, 1997).…”

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confidence: 99%

Extensive molecular screening for hereditary non-polyposis colorectal cancer

et al. 2000

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The genetic abnormalities underlying hereditary non-polyposis colorectal cancer (HNPCC) are germline mutations in one of five DNA mismatch repair genes or in the TGFβRII gene. The aim of our study was to evaluate the significance of simple tests performed on tumours to select appropriate candidates for germline mutational analysis. We studied three groups of patients, HNPCC kindreds fulfilling the International Collaborative Group (ICG) criteria ( n = 10), families in which at least one of the criteria was not satisfied ( n = 7) and sporadic colorectal cancer (CRC) diagnosed before the age of 50 ( n = 17). We searched for microsatellite instability (MSI), presence of hMSH2 and hMLH1 germline mutations, expression of hMSH2, hMLH1 and p53 proteins in tumoural tissue samples by immunostaining. Fifteen out of 17 (88%) of HNPCC and incomplete HNPCC cases were MSI and eight pathogenic germline mutations in hMSH2 or hMLH1 were detected in these two groups (53%). All the 17 early-onset sporadic cases were MSS and no germline mutations were detected among the seven investigated cases. Thirteen out of 15 (81%) familial cases were MSI and p53 protein-negative, whereas 13/14 (93%) sporadic cases were MSS and strongly p53 protein-positive. This extensive molecular investigation shows that simple tests such as MS study combined with hMSH2 and hMLH1 protein immunostaining performed on tumoural tissues may provide valuable information to distinguish between familial, and probably hereditary, and sporadic CRC cases. © 2000 Cancer Research Campaign

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A Naturally Occurring hPMS2 Mutation Can Confer a Dominant Negative Mutator Phenotype

Cited by 87 publications

References 30 publications

Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours

Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

Extensive molecular screening for hereditary non-polyposis colorectal cancer

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