MSH2 andMLH1 mutations in sporadic replication error-positive colorectal carcinoma as assessed by two-dimensional DNA electrophoresis

Wu, Ying; Nyström‐Lahti, Minna; Osinga, Jan; Looman, Maaike W. G.; Peltomäki, Païvi; Aaltonen, LA; Delachapelle, A; Hofstra, Robert; Buys, Chcm

doi:10.1002/(sici)1098-2264(199704)18:4<269::aid-gcc4>3.0.co;2-z

Cited by 101 publications

(12 citation statements)

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“…This study Risinger et al (1996) Risinger et al (1996 N-MSH6-1F MSH6-1F MSH6-1R Originates from a family meeting the Amsterdam criteria for HNPCC (Vasen et al, 1991); f Loss of heterozygosity observed in tumor (Hemminki et al, 1994;Wu et al, 1997) with`severe' RER (n=33), 22 of which were known to have somatic and/or germline mutations in MSH2 or MLH1 while no mutations in these genes had been identi®ed in 11 (NystroÈ m-Lahti et al, 1996;Wu et al, 1997;Aaltonen et al, 1998) (Figure 1a). Interestingly, the overall mutation rates, expressed as the proportions of mutated loci among all studied MSH3, MSH6, BAX, and TGFb RII loci, varied remarkably between these groups in that`mild' RER tumors showed no mutations at all whereas in tumors with`severe' RER, the rate was signi®cantly higher in those showing MSH2 or MLH1 mutations, compared to the remaining tumors with a similar RER phenotype (46/ 88, 52% vs 11/44, 25%, P=0.005) ( Table 3).…”

Section: Msh3 Msh6 Bax and Tgfb Rii Mutations In`mild' And`severe' mentioning

confidence: 99%

“…Typical RER Thirty-three colorectal tumors were investigated, 22 of which were known to have germline and/or somatic mutations in MSH2 or MLH1, whereas no such mutations had been detected in 11 (Wu et al, 1997;NystroÈ m-Lahti et al, 1996;Aaltonen et al, 1998).…”

Section: Tumor Selectionmentioning

confidence: 99%

“…Tumors with dramatic changes at a single locus often show a widespread instability at most of the studied microsatellite loci; they share certain clinical and pathological features like proximal location in the colon, poor dierentiation, and better prognosis (Thibodeau et al, 1993;Ionov et al, 1993;Lothe et al, 1993;Kim et al, 1994). This pattern characterizes Hereditary Nonpolyposis Colorectal Carcinoma (HNPCC) tumors and around 10% of sporadic colorectal cancers, and is associated with mutations in MSH2, MLH1, or PMS2 in most tumors from the HNPCC group and in one-third of tumors from the sporadic group (Bùrresen et al, 1995;Liu et al, 1996;Konishi et al, 1996;Wu et al, 1997). Less clear are the role and the mechanisms underlying lowlevel microsatellite instability.…”

Section: Introductionmentioning

confidence: 99%

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Mismatch repair genes and mononucleotide tracts as mutation targets in colorectal tumors with different degrees of microsatellite instability

et al. 1998

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Microsatellite instability occurs in 15% of colorectal carcinomas and may be due to replication errors (RER). The pattern of instability ±`severe' vs`mild' ± and the tumorigenic pathway, as re¯ected by the involvement of functionally important genes, may vary according to the underlying gene(s). We de®ned`mild' RER as mono-or tetranucleotide repeat instability in the absence of widespread instability at dinucleotide repeats and studied 15 colorectal tumors with this phenotype for mutations in the DNA mismatch repair genes MSH2, MLH1, MSH3, and MSH6. No mutations were found, suggesting that these genes were not implicated. We then compared colorectal cancers with`mild' RER (n=15), and those with`severe' RER without (n=11) or with (n=22) detectable mutations in MSH2 or MLH1 to assess the involvement of mononucleotide repeats contained in the coding regions of MSH3, MSH6, BAX, and TGFb RII. The combined mutation rates of the above mentioned loci varied signi®cantly between the three groups of tumors, being 0%, 25% and 52%, respectively. Furthermore, the individual genes showed speci®c patterns of involvement; for example, among tumors with`severe' RER, TGFb RII displayed uniformly high mutation rates while MSH3, MSH6, and BAX were more frequently altered in tumors that also showed MSH2 or MLH1 mutations. Our ®ndings suggest that dierent subcategories exist among unstable tumors, de®ned by the RER pattern on the one hand and tumorigenic pathway on the other, and structural changes of MSH2 and MLH1 are likely to explain only a proportion of these cases.

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Section: Msh3 Msh6 Bax and Tgfb Rii Mutations In`mild' And`severe' mentioning

confidence: 99%

Section: Tumor Selectionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mismatch repair genes and mononucleotide tracts as mutation targets in colorectal tumors with different degrees of microsatellite instability

et al. 1998

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“…Among the MMR genes, the hMSH2 or the hMLH1 gene is most frequently mutated in HNPCC patients (Liu et al, 1996;Weber et al, 1997). However, in many types of sporadic cancers hMSH2 or hMLH1 mutation is rare (Herfarth et al, 1997;Kowalski et al, 1997;Liu et al, 1995;Thibodeau et al, 1996;Wu et al, 1997b). Moreover, mutations in MMR genes have no marked hot-spots such as ones in the p53 gene (Beck et al, 1997;Liu et al, 1996;Nystrom-Lahti et al, 1996;Weber et al, 1997) and MMR genes sometimes undergo epigenetic silencing (Ahuja et al, 1997).…”

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confidence: 99%

Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair

et al. 1999

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Mutations in DNA mismatch repair (MMR) genes in hereditary non-polyposis colon cancer (HNPCC) patients revealed the importance of MMR de®ciency as a risk for carcinogenesis. Since diverse mutations occur in several MMR genes, the instability of repeat sequences dispersed in the genome, which are also governed by the MMR system, is a well used marker. However, the relationship between repeat sequence instability and MMR gene mutation in human cells has not been well de®ned mainly because precise systems to analyse repeat sequences have not been available. Using our newly developed system, we analysed alteration of dinucleotide repeats in human cell lines which harbour mutations in MMR genes. Among 24 subclones of DLD-1 cells (hMSH6 7 ) only one had a dinucleotide repeat alteration in only one microsatellite locus, while LoVo cells (hMSH2 7 /hMSH6 7 ) exhibited marked dinucleotide repeat instability (DRI). HCT116 cells, a hMLH1-mutant, showed an ultimate DRI phenotype. Interestingly, SW48 cells lacking hMLH1 expression also demonstrated DRI, albeit the extent of diversity being signi®cantly lower than HCT116. These data suggest that the DRI phenotype in human cells is highly dependent on mutated MMR genes and on forms of mutation. The results of DRI analyses used to detect MMR-de®ciency should be interpreted with caution.

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“…PCR amplification of RET exons 1 and 4 and a part of MSH6 exon 1 was carried out as previously described (15,16). A 60 bp GC clamp was attached to one of the primers.…”

Section: Dna Amplificationmentioning

confidence: 99%

Improved mutation detection in GC-rich DNA fragments by combined DGGE and CDGE

Wu¹

1999

Nucleic Acids Research

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Denaturing gradient gel electrophoresis (DGGE) has proven to be a powerful pre-screening method for the detection of DNA variants. If such variants occur, however, in DNA fragments that are very rich in G and C, they may escape detection. To overcome this limitation, we tested a novel gel system which combines DGGE and constant denaturant gel electrophoresis (CDGE), as it might have the advantages of both methods. Indeed, this combination had the advantages of both methods, good separation of heteroduplex molecules and prevention of total strand dissociation, and it proved successful in the detection of DNA variants in several GC-rich fragments.

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MSH2 andMLH1 mutations in sporadic replication error-positive colorectal carcinoma as assessed by two-dimensional DNA electrophoresis

Cited by 101 publications

References 26 publications

Mismatch repair genes and mononucleotide tracts as mutation targets in colorectal tumors with different degrees of microsatellite instability

Mismatch repair genes and mononucleotide tracts as mutation targets in colorectal tumors with different degrees of microsatellite instability

Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair

Improved mutation detection in GC-rich DNA fragments by combined DGGE and CDGE

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