Mismatch Repair Deficiency in Phenotypically Normal Human Cells

Parsons, Ramon; Li, Guo Min; Longley, Matthew J.; Modrich, Paul; Liu, Bo; Berk, T.; Hamilton, Stanley R.; Kinzler, Kenneth W.; Vogelstein, Bert

doi:10.1126/science.7632227

Cited by 282 publications

(148 citation statements)

References 29 publications

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“…Homozygous knockouts of MMR genes can elevate mutation rates by as much as 100-fold, whereas the effects in heterozygotes are much more modest, again implying partial dominance (' 10% penetrance) (Borgdorff et al 2005;Hegan et al 2006;Burr et al 2007). On the other hand, consistent with the observations on heterologous systems noted above, the degree of dominance for missense mutations with moderate effects on repair efficiency can be much more pronounced (Parsons et al 1995;Drotschmann et al 1999), with some data suggesting that heterozygous mammalian carriers of missense mutations at MMR loci have mutation rates elevated by factors of 5-10 (Coolbaugh- Murphy et al 2004;Alazzouzi et al 2005).…”

Section: Expected Frequency Of Detrimental Alleles For Replication/resupporting

confidence: 76%

The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution

2008

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Although the matter has been subject to considerable theoretical study, there are numerous open questions regarding the mechanisms driving the mutation rate in various phylogenetic lineages. Most notably, empirical evidence indicates that mutation rates are elevated in multicellular species relative to unicellular eukaryotes and prokaryotes, even on a per-cell division basis, despite the need for the avoidance of somatic damage and the accumulation of germline mutations. Here it is suggested that multicellularity discourages selection against weak mutator alleles for reasons associated with both the cellular and the population-genetic environments, thereby magnifying the vulnerability to somatic mutations (cancer) and increasing the risk of extinction from the accumulation of germline mutations. Moreover, contrary to common belief, a cost of fidelity need not be invoked to explain the lower bound to observed mutation rates, which instead may simply be set by the inability of selection to advance very weakly advantageous antimutator alleles in finite populations.

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Section: Expected Frequency Of Detrimental Alleles For Replication/resupporting

confidence: 76%

The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution

2008

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“…The presence of a mutator phenotype, similar to that observed in Hereditary Non-Polyposis Colon Cancer (HNPCC) and gastric carcinomas was investigated by searching for frameshift mutations in TGF-b type IIR and Bax. Mutations in polypurine tracts within these genes have been reported in human tumours, such as gastric carcinoma, with MSI Parsons et al, 1995;Chung et al, 1997). However, the absence of any such changes in the BRCA-associated tumours in the present series implies that a classical mutator phenotype is not present in BRCA-associated tumours.…”

Section: Discussioncontrasting

confidence: 64%

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

et al. 1998

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The status of p53 was investigated in breast tumours arising in germ-line carriers of mutant alleles of BRCA1 and BRCA2 and in a control series of sporadic breast tumours. p53 expression was detected in 20/26 (77%) BRCA1-, 10/22 (45%) BRCA2-associated and 25/72 (35%) grade-matched sporadic tumours. Analysis of p53 sequence revealed that the gene was mutant in 33/50 (66%) BRCA-associated tumours, whereas 7/20 (35%) sporadic grade-matched tumours contained p53 mutation (P50.05). A number of the mutations detected in the BRCA-associated tumours have not been previously described in human cancer databases, whilst others occur extremely rarely. Analysis of additional genes, p16 INK4 , Ki-ras and b-globin revealed absence or very low incidence of mutations, suggesting that the higher frequency of p53 mutation in the BRCA-associated tumours does not re¯ect a generalized increase in susceptibility to the acquisition of somatic mutation. Furthermore, absence of frameshift mutations in the polypurine tracts present in the coding sequence of the TGF b type II receptor (TGF b IIR) and Bax implies that loss of function of BRCA1 or BRCA2 does not confer a mutator phenotype such as that found in tumours with microsatellite instability (MSI). p21 Waf1 was expressed in BRCA-associated tumours regardless of p53 status and, furthermore, some tumours expressing wild-type p53 did not express detectable p21 Waf1 . These data do not support, therefore, the simple model based on studies of BRCA7/7 embryos, in which mutation of p53 in BRCA-associated tumours results in loss of p21 Waf1 expression and deregulated proliferation. Rather, they imply that proliferation of such tumours will be subject to multiple mechanisms of growth regulation.

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“…In HNPCC, defective MMR is a very early event (Parsons et al, 1995), while in sporadic non-small cell lung carcinoma it has been suggested that defective MMR is a later event related to lung tumour progression (Wieland et al, 1996). The present study suggests that MMR deficiency in bladder cancer is likely to occur during tumour progression rather than as an initiating event since the majority of the samples analysed revealed intratumoral heterogeneity in expression of MMR proteins rather than complete loss in all cells of the tumour.…”

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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Mismatch Repair Deficiency in Phenotypically Normal Human Cells

Cited by 282 publications

References 29 publications

The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution

The Cellular, Developmental and Population-Genetic Determinants of Mutation-Rate Evolution

p53 mutation with frequent novel codons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours

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

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