A new variant database for mismatch repair genes associated with Lynch syndrome

Woods, Michael O.; Williams, Phillip; Careen, Amanda; Edwards, Laura; Bartlett, Sylvia E.; McLaughlin, John; Younghusband, H. Banfield

doi:10.1002/humu.20502

Cited by 109 publications

(94 citation statements)

References 27 publications

(25 reference statements)

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“…Consistent with the central role of MutS␣ in detecting and signaling responses to mismatched and damaged DNA, the loss of MSH2 or MSH6 activity results in accumulation of somatic mutations in tumor cells and resistance to the genotoxic effects of many DNA damaging agents (4,21). Edelmann and co-workers generated two knock-in mouse strains harboring Msh2 G674A or Msh6 T1217D alleles and found that the mice developed cancer, exhibited microsatellite instability, and yielded embryonic fibroblasts that displayed impaired MMR in vitro.…”

Section: The Heterodimeric Human Msh2-msh6 Protein Initiates Dna Mismmentioning

confidence: 84%

Biochemical Analysis of the Human Mismatch Repair Proteins hMutSα MSH2G674A-MSH6 and MSH2-MSH6T1219D

Geng

Sakato

DeRocco

et al. 2012

Journal of Biological Chemistry

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Background: MutS␣, a heterodimer of MSH2 and MSH6, is essential for DNA mismatch repair. Results: hMsh2 G674A -hMSH6 wt and hMSH2 wt -hMSH6 T1219D mutant proteins fail to efficiently license mismatch-provoked, nick-directed excision. Conclusion: Different defects underlie the apparently similar repair deficiency of these two mutants. Significance: Findings provide new insights into the mechanism of mismatch repair with implications for cancer predisposition and the apoptotic response to DNA damaging agents.

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Section: The Heterodimeric Human Msh2-msh6 Protein Initiates Dna Mismmentioning

confidence: 84%

Biochemical Analysis of the Human Mismatch Repair Proteins hMutSα MSH2G674A-MSH6 and MSH2-MSH6T1219D

Geng

Sakato

DeRocco

et al. 2012

Journal of Biological Chemistry

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“…The rest are sporadic cases caused by the hypermethylation of the MLH1 gene promoter 82 . More than 1, 500 germline variants have been found in the MMR genes along with promoter methylation, somatic deletions, or point mutations [85][86][87] . The germline hypermethylations in MLH1 and MSH2 may also increase susceptibility [88][89][90] .…”

Section: Microsatellite Instabilitymentioning

confidence: 99%

Colorectal cancer carcinogenesis: a review of mechanisms

Tariq¹,

Ghias²

2016

Cancer Biology &Amp; Medicine

220

138

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Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men globally. CRC arises from one or a combination of chromosomal instability, CpG island methylator phenotype, and microsatellite instability. Genetic instability is usually caused by aneuploidy and loss of heterozygosity. Mutations in the tumor suppressor or cell cycle genes may also lead to cellular transformation. Similarly, epigenetic and/or genetic alterations resulting in impaired cellular pathways, such as DNA repair mechanism, may lead to microsatellite instability and mutator phenotype. Non-coding RNAs, more importantly microRNAs and long non-coding RNAs have also been implicated at various CRC stages. Understanding the specific mechanisms of tumorigenesis and the underlying genetic and epigenetic traits is critical in comprehending the disease phenotype. This paper reviews these mechanisms along with the roles of various non-coding RNAs in CRCs.

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“…[17][18][19] Of the cases with loss of MSH2 immunohistochemical staining, approximately twothirds of identifiable mutations in MSH2 are point mutations or small insertions and deletions, whereas the remaining one-third are large gene rearrangements and deletions. 20,21 However, mutations in MSH2 are not identified in up to 20% of the cases expected to have such an alteration.…”

mentioning

confidence: 99%

Frequency of Deletions of EPCAM (TACSTD1) in MSH2-Associated Lynch Syndrome Cases

Rumilla

Schowalter

Lindor

et al. 2011

The Journal of Molecular Diagnostics

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Lynch syndrome is an autosomal dominant cancer predisposition syndrome characterized by loss of function of DNA mismatch repair enzyme MLH1, MSH2, MSH6, or PMS2. Mutations in MLH1 and MSH2 account for ϳ80% of the inherited cases. However, in up to 20% of cases suspected of having a germline mutation in MSH2 due to loss of MSH2 expression, a germline mutation is not identified. Recent studies have shown that some Lynch syndrome cases are due to 3= EPCAM/TACSTD1 deletions that subsequently lead to MSH2 promoter hypermethylation. In this study, we examined the frequency of this novel mechanism for MSH2 inactivation in cases recruited through the Colon Cancer Family Registry and from the Mayo Clinic Molecular Diagnostics Laboratory. From the combined cohort, 58 cases were selected in which immunohistochemical staining suggested a mutation in MSH2 or MSH6, but no mutations were identified on follow-up testing. Of these 58 cases, 11 demonstrated a deletion of EPCAM/TACSTD1. Of cases with a deletion, the methylation status of the MSH2 promoter was confirmed in tumor tissue using methylation-sensitive PCR primers. One case showed MSH2 promoter hypermethylation in the absence of a detectable EPCAM/TACSTD1 deletion. These results indicate that approximately 20% to 25% of cases suspected of having a mutation in MSH2 but in which a germline mutation is not detected, can be accounted for by germline deletions in EPCAM/TACSTD1. These data also suggest the presence of other alterations leading to MSH2 promoter hypermethylation. Lynch syndrome is an autosomal dominant predisposition syndrome in which patients have a propensity to develop colorectal adenocarcinoma, endometrial carcinoma, sebaceous neoplasms, upper urinary tract urothelial carcinomas, central nervous system neoplasms, and ovarian and hepatobiliary neoplasms.1-4 The underlying genetic basis for this syndrome is the presence of a mutation in one of the DNA mismatch repair genes MLH1, MSH2, MSH6 or PMS2. [5][6][7][8][9][10] The defining phenotype of tumors from these patients is the presence of tumor microsatellite instability [11][12][13] and loss of protein expression of the affected enzyme in the tumor nuclei as detected by immunohistochemical staining.14 -16 The spectrum of mu-

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A new variant database for mismatch repair genes associated with Lynch syndrome

Cited by 109 publications

References 27 publications

Biochemical Analysis of the Human Mismatch Repair Proteins hMutSα MSH2G674A-MSH6 and MSH2-MSH6T1219D

Biochemical Analysis of the Human Mismatch Repair Proteins hMutSα MSH2G674A-MSH6 and MSH2-MSH6T1219D

Colorectal cancer carcinogenesis: a review of mechanisms

Frequency of Deletions of EPCAM (TACSTD1) in MSH2-Associated Lynch Syndrome Cases

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