Two mismatch repair gene mutations found in a colon cancer patient – which one is pathogenic?

Kariola, Reetta; Otway, Robyn; Lönnqvist, Karin E.; Raevaara, Tiina E.; Macrae, Finlay; Vos, Yvonne J.; Kohonen‐Corish, Maija; Hofstra, Robert M.W.; Nyström, Minna

doi:10.1007/s00439-002-0866-4

Cited by 31 publications

(38 citation statements)

References 17 publications

(23 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In our study, two patients concurrently carrying two MMR base substitutions each had two siblings, but no parents, who had colon cancer. A similar inheritance pattern has been observed in two families with two concurrent MMR missense mutations, suggesting recessive rather than dominant inheritance (30).…”

Section: Discussionsupporting

confidence: 74%

“…Some missense mutations may be associated with a familial predisposition to colorectal cancer, whereas others may be non-functioning polymorphisms, as shown in population-based and functional studies (24,29). MMR genes and other genes involved in DNA replication may cause a strong mutator phenotype when they are combined with each other, as in the two patients of our study, although each of these individual alleles may give rise to a weak mutator phenotype (30). Mutation prevalence in our study was 6%, including polymorphism and splicing substitution.…”

Section: Discussionsupporting

confidence: 55%

“…In other words, associations among horizontal generations would be similar to those among successive generations in familial colorectal cancer. Segregation analysis of families without MMR mutations has suggested the existence of a moderately rare, recessively inherited disease allele (10,11,30). In our study, two patients concurrently carrying two MMR base substitutions each had two siblings, but no parents, who had colon cancer.…”

Section: Discussionmentioning

confidence: 53%

See 2 more Smart Citations

Characterization of Mutator Phenotype in Familial Colorectal Cancer Patients Not Fulfilling Amsterdam Criteria

Kim¹,

Lee²,

Ka³

et al. 2004

Clinical Cancer Research

View full text Add to dashboard Cite

Purpose: Although the mutator phenotype, including genetic and epigenetic alterations of the mismatch repair (MMR) system, seems to be pronounced in familial colorectal cancer, there have been few integrative studies comprising the entire mutator pathway. This study was done to identify the entire mutator pathway determining risk factors in patients with familial colorectal cancer not fulfilling the Amsterdam criteria.Experimental Design: We consecutively recruited 134 colorectal cancer patients with a family history of accompanying cancers. Patients with hereditary nonpolyposis colorectal cancer meeting the Amsterdam criteria, familial adenomatous polyposis, or those receiving preoperative radiotherapy were excluded. Mutator phenotype was assessed by assaying microsatellite instability (MSI) at 24 markers, hMLH1-promoter methylation, mutations at MMR genes (hMLH1, hMSH2, hMSH6, and hPMS2), and immune staining of MMR proteins (hMLH1, hMSH2, hMSH6, hPMS1, and hPMS2).Results: Of the 208 cancers in first-degree and/or second-degree relatives of patients, colorectal and gastric cancers (81%) were most common. Of the 134 proband colorectal cancers, 23 (17%) were MSI in high level, and 32 (24%) were MSI in low level. MMR alterations, including known polymorphism and splicing substitution, were identified in eight patients (6%). Twenty-eight tumors with mutator phenotype were further identified by hMLH1-promoter methylation and/or loss of MMR protein expression. In 51 tumors (38%), mutator phenotype was associated with right-sided colon cancer (P < 0.001) and younger age at onset (P ‫؍‬ 0.032), but the number of patients with a mutator phenotype did not differ with respect to inheritance patterns of accompanying cancers, either successive or horizontal transmission (P ‫؍‬ 0.815). Familial impact value, which differentially associated the degree of relatives with all accompanying cancers, effectively discriminated MSI in high level from microsatellite stable/MSI in low level tumors.Conclusion: Familial colorectal cancer may be associated with multiple occurrences of colorectal or accompanying cancers inherited by dominant or recessive transmission. MMR gene mutations, however, are less associated with mutator phenotype in familial colorectal cancer.

show abstract

Section: Discussionsupporting

confidence: 74%

Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 53%

See 1 more Smart Citation

Characterization of Mutator Phenotype in Familial Colorectal Cancer Patients Not Fulfilling Amsterdam Criteria

Kim¹,

Lee²,

Ka³

et al. 2004

Clinical Cancer Research

View full text Add to dashboard Cite

show abstract

“…In almost half of families with HNPCC, a germline mutation in a MMR gene has not been identified, and some familial cancers resemble HNPCC but do not display the typical, dominant inheritance pattern (18). For example, Kariola et al (30) identified two independent HNPCC families in which the affected individuals had one mutation in hMSH2 and another in hMSH6. Inheritance of HNPCC in these families appeared to be recessive.…”

Section: Discussionmentioning

confidence: 99%

Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair

Heck

Argueso²,

Gemici³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

113

View full text Add to dashboard Cite

In budding yeast, the MLH1-PMS1 heterodimer is the major MutL homolog complex that acts to repair mismatches arising during DNA replication. Using a highly sensitive mutator assay, we observed that Saccharomyces cerevisiae strains bearing the S288c-strain-derived MLH1 gene and the SK1-strain-derived PMS1 gene displayed elevated mutation rates that conferred a long-term fitness cost. Dissection of this negative epistatic interaction using S288c-SK1 chimeras revealed that a single amino acid polymorphism in each gene accounts for this mismatch repair defect. Were these strains to cross in natural populations, segregation of alleles would generate a mutator phenotype that, although potentially transiently adaptive, would ultimately be selected against because of the accumulation of deleterious mutations. Such fitness ''incompatibilities'' could potentially contribute to reproductive isolation among geographically dispersed yeast. This same segregational mutator phenotype suggests a mechanism to explain some cases of a human cancer susceptibility syndrome known as hereditary nonpolyposis colorectal cancer, as well as some sporadic cancers.colorectal cancer ͉ incompatibility T he highly conserved mismatch repair (MMR) system contributes to genome stability by repairing errors that occur during DNA replication (1). In Escherichia coli, MMR is initiated by the binding of MutS protein to DNA mismatches. MutL interacts with the MutS-mismatch complex and activates downstream repair factors. Multiple MutS homologs (MSH) and MutL homologs (MLH) have evolved in eukaryotes that form heterodimers with specialized functions in DNA repair and recombination (2, 3). In Saccharomyces cerevisiae, MSH2-MSH3 and MSH2-MSH6 function in mismatch recognition, and MLH1-PMS1 is the primary MLH heterodimer in postreplicative MMR. Mutations in MSH and MLH genes that act in MMR elevate mutation rate, as measured in reversion and forward mutation assays, and reduce spore viability of diploid cells due to the accumulation of recessive lethal mutations (4-6). In addition, MMR proteins act to prevent recombination between divergent DNA sequences. This activity has been shown to prevent chromosomal rearrangements (7,8) and to enforce reproductive barriers between species (9, 10).Previously we created 60 alleles of the S. cerevisiae MLH1 gene from the S288c strain (cMLH1) in which clusters of charged residues were simultaneously changed to Ala (11). These alleles were tested for defects in MMR in the S288c (12) and SK1 (13) strains. More than one-third of the mutation set conferred a more severe MMR defect in SK1 strains than in S288c strains. Two mutations, cmlh1-29 and cmlh1-56, conferred wild-type-like phenotypes in S288c but null-like phenotypes in SK1. Introduction of the S288c PMS1 gene into the SK1 strain suppressed the mutator phenotype of these mutants, suggesting that the MMR phenotype was due to incompatibility, or negative epistasis, between MLH components (11).The influences of epistatic interactions on a wide variety of traits and proc...

show abstract

“…Mutations in at least four mismatch repair (MMR) genes, MLH1, MSH2, MSH6 and PMS2, result in Lynch syndrome, or HNPCC (hereditary nonpolyposis colorectal cancer); together these MMR gene mutations account for 3-5% of all CRC [1][2][3]. Given the relatively high incidence of these conditions, one would expect an occasional individual to be homozygous for the two APC or two MMR mutations, or to be a carrier of compound heterozygous germline mutations in APC and MMR genes [4][5][6][7][8][9] Table 1.…”

Section: Introductionmentioning

confidence: 99%

Double frameshift mutations in APC and MSH2 in the same individual

Soravia

Delozier

Dobbie³

et al. 2005

Int J Colorectal Dis

View full text Add to dashboard Cite

show abstract

Two mismatch repair gene mutations found in a colon cancer patient – which one is pathogenic?

Cited by 31 publications

References 17 publications

Characterization of Mutator Phenotype in Familial Colorectal Cancer Patients Not Fulfilling Amsterdam Criteria

Characterization of Mutator Phenotype in Familial Colorectal Cancer Patients Not Fulfilling Amsterdam Criteria

Negative epistasis between natural variants of the Saccharomyces cerevisiae MLH1 and PMS1 genes results in a defect in mismatch repair

Double frameshift mutations in APC and MSH2 in the same individual

Contact Info

Product

Resources

About