Stepwise Deletions of PolyA Sequences in Mismatch Repair-Deficient Colorectal Cancers

Blake, Corey; Tsao, Jen‐Lan; Wu, Anna H.; Shibata, Darryl

doi:10.1016/s0002-9440(10)64143-0

Cited by 35 publications

(30 citation statements)

References 20 publications

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“…For BAT-25 and BAT-26, the average shift was Ϫ5.4 and Ϫ8.8 bases, respectively, which is remarkably consistent with previous data demonstrating average deletions of these markers in MSIϩ cancers of Ϫ5.3 and Ϫ9 bases, respectively. 23 The average shift for NR21, Mono27, and NR24 was Ϫ6.9, Ϫ5.6, and Ϫ7.3 bases, respectively. Thus, it appears that shifts to larger size products for each of these five mononucleotide loci are uncommon.…”

Section: Resultsmentioning

confidence: 93%

“…The shifts for all five mononucleotide loci in the 11 MSI-high cases resulted in products that were smaller in size than the germline allele, which is consistent with the data of others demonstrating that deletions in polyA sequences are much more common than insertions. 22,23 Although the dominant novel product lengths varied from 2 to 12 bases smaller than the germline allele length, shifts to dominant allele sizes that were 6 to 8 bases smaller than the germline allele were most frequent when all markers are considered. For BAT-25 and BAT-26, the average shift was Ϫ5.4 and Ϫ8.8 bases, respectively, which is remarkably consistent with previous data demonstrating average deletions of these markers in MSIϩ cancers of Ϫ5.3 and Ϫ9 bases, respectively.…”

Section: Resultsmentioning

confidence: 99%

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Comparison of the Microsatellite Instability Analysis System and the Bethesda Panel for the Determination of Microsatellite Instability in Colorectal Cancers

Murphy

Zhang

Geiger

et al. 2006

The Journal of Molecular Diagnostics

245

174

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Microsatellite instability (MSI) analysis of colorectal cancers is clinically useful to identify patients with hereditary nonpolyposis colorectal cancer (HNPCC)caused by germline mutations of mismatch repair genes. MSI status may also predict cancer response/ resistance to certain chemotherapies. We evaluated the MSI Analysis System (Promega Corp.; five mononucleotide and two pentanucleotide repeats) and compared the results to the Bethesda panel, which interrogates five microsatellite loci recommended by the 1997 National Cancer Institute-sponsored MSI workshop (three dinucleotide and two mononucleotide repeats). Thirty-four colorectal cancers were analyzed by both assays. The overall concordance between the two assays was 85% (29 of 34). There was complete concordance between the two assays for all of the MSI-high (11 of 11) and microsatellite stable (MSS; 18 of 18) cases. In the 11 MSI-high cases, all 5 of the mononucleotide loci in the MSI Analysis System demonstrated shifted alleles (100% sensitivity), and each shift resulted in products that were smaller in size than the germline alleles. All (5 of 5) of the cases interpreted as MSI-low by the Bethesda assay were interpreted as MSS by the MSI Analysis System. Our results suggest that the MSI Analysis System is generally superior and may help resolve cases of MSI-low into either MSI-high or MSS.

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Section: Resultsmentioning

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Comparison of the Microsatellite Instability Analysis System and the Bethesda Panel for the Determination of Microsatellite Instability in Colorectal Cancers

Murphy

Zhang

Geiger

et al. 2006

The Journal of Molecular Diagnostics

245

174

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“…The shifts for all mononucleotide loci in the MSI-H cases resulted in products that were smaller in size than the germline allele, which is consistent with data of others demonstrating that deletions in poly(A) sequences are much more common than insertions. 6,23,24 The one MSI-H case solely instable in two of the dinucleotide markers of the Bethesda panel showed stability in all four mononucleotide markers. This strongly suggests the sample may represent a MSS tumor misclassified by the dinucleotide markers of the Bethesda panel, a phenomenon that has been described previously.…”

Section: Discussionmentioning

confidence: 96%

Detection of Microsatellite Instability in Colorectal Cancer Using an Alternative Multiplex Assay of Quasi-Monomorphic Mononucleotide Markers

Deschoolmeester

Baay

Wuyts

et al. 2008

The Journal of Molecular Diagnostics

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Colorectal malignancies demonstrating microsatellite instability (MSI) have a very heterogeneous histological appearance, better prognosis, and altered response to therapy. Consequently, identification of the MSI phenotype is both relevant and interesting as a screening and prognostic tool and as a potential predictive factor of chemotherapeutic response. Several groups have argued for the exclusive use of mononucleotide markers for MSI analysis. In this study, an alternative MSI typing multiplex system of mononucleotide microsatellite repeats was developed. This system obviates the need to compare allelic profiles between tumor and matching normal DNA, rendering MSI analysis amenable to high throughput. The quasi-monomorphic allelic distribution of five alternative mononucleotide markers was evaluated in genomic DNA. Only SEC63 and CAT25 were found to be quasi-monomorphic and were thus combined with BAT25 and BAT26 from the Bethesda panel. Consequently, 177 colorectal cancer samples previously analyzed by the Bethesda panel were tested for MSI using this alternative mononucleotide panel. In an attempt to resolve discordant cases, immunohistochemistry of MLH1, MSH2, and MSH6 was performed. The concordance between both panels reached 99.4% when microsatellite stability and MSI-L were grouped together. These new markers were subsequently multiplexed in a single polymerase chain reaction assay. The resulting mononucleotide fluorescent multiplex MSI assay has high accuracy, reliability, and throughput, thus reducing the time and cost involved in MSI testing. (J Mol Diagn

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“…The observations that slip-outs of one to three excess repeats require MutSβ for repair and that perturbation of MutSβ levels can reduce repair suggest that the increment of change during a single mutagenic step would be one to three excess repeats. Limited evidence from patient tissues supports incremental changes of 1 to 3 CTG/CAG units per mutation event (48)(49)(50)(51), similar to that occurring at other simple repeats such as (CA)n and (A)n (52,53).…”

Section: Discussionmentioning

confidence: 99%

Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSβ, but clustered slip-outs are poorly repaired

Panigrahi

Slean

Simard

et al. 2010

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

137

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Expansions of CTG/CAG trinucleotide repeats, thought to involve slipped DNAs at the repeats, cause numerous diseases including myotonic dystrophy and Huntington's disease. By unknown mechanisms, further repeat expansions in transgenic mice carrying expanded CTG/CAG tracts require the mismatch repair (MMR) proteins MSH2 and MSH3, forming the MutSβ complex. Using an in vitro repair assay, we investigated the effect of slip-out size, with lengths of 1, 3, or 20 excess CTG repeats, as well as the effect of the number of slip-outs per molecule, on the requirement for human MMR. Long slip-outs escaped repair, whereas short slip-outs were repaired efficiently, much greater than a G-T mismatch, but required hMutSβ. Higher or lower levels of hMutSβ or its complete absence were detrimental to proper repair of short slip-outs. Surprisingly, clusters of as many as 62 short slip-outs (one to three repeat units each) along a single DNA molecule with (CTG)50•(CAG)50 repeats were refractory to repair, and repair efficiency was reduced further without MMR. Consistent with the MutSβ requirement for instability, hMutSβ is required to process isolated short slip-outs; however, multiple adjacent short slip-outs block each other's repair, possibly acting as roadblocks to progression of repair and allowing error-prone repair. Results suggest that expansions can arise by escaped repair of long slip-outs, tandem short slip-outs, or isolated short slip-outs; the latter two types are sensitive to hMutSβ. Poor repair of clustered DNA lesions has previously been associated only with ionizing radiation damage. Our results extend this interference in repair to neurodegenerative disease-causing mutations in which clustered slip-outs escape proper repair and lead to expansions.

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Stepwise Deletions of PolyA Sequences in Mismatch Repair-Deficient Colorectal Cancers

Cited by 35 publications

References 20 publications

Comparison of the Microsatellite Instability Analysis System and the Bethesda Panel for the Determination of Microsatellite Instability in Colorectal Cancers

Comparison of the Microsatellite Instability Analysis System and the Bethesda Panel for the Determination of Microsatellite Instability in Colorectal Cancers

Detection of Microsatellite Instability in Colorectal Cancer Using an Alternative Multiplex Assay of Quasi-Monomorphic Mononucleotide Markers

Isolated short CTG/CAG DNA slip-outs are repaired efficiently by hMutSβ, but clustered slip-outs are poorly repaired

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