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

Murphy, Kathleen M.; Zhang, Shengle; Geiger, Tanya; Hafez, Michael J.; Bacher, Jeffery W.; Berg, Karin D.; Eshleman, James R.

doi:10.2353/jmoldx.2006.050092

Cited by 245 publications

(185 citation statements)

References 28 publications

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“…71 Instability of only 1 of 5 markers, termed MSI-low or indeterminate, is observed more frequently using the Bethesda panel, and many such cases are actually microsatellite stable with the MSI Analysis System. 72 Although there is controversy regarding the biologic significance of MSI-low, it does not appear to be a useful marker for LS. Microsatellite instability at selected trinucleotide and tetranucleotide repeats is a distinct entity in noncolonic tumors and is unrelated to LS.…”

Section: Members the Evaluation Of Genomic Applications Inmentioning

confidence: 99%

Microsatellite Instability and Colorectal Cancer

Geiersbach¹,

Samowitz²

2011

Archives of Pathology &Amp; Laboratory Medicine

121

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Context.—About 15% of colorectal cancers are characterized by genomic microsatellite instability, and of these, about 1 in 5 (2%–4% overall) are due to Lynch syndrome, a dominantly inherited condition predisposing the patient to cancers of multiple organ systems, including the gastrointestinal tract. Identification of individuals with Lynch syndrome allows for increased surveillance of the affected individual and of potentially affected family members. Objective.—To review the literature on microsatellite instability in colorectal cancer and current laboratory diagnostic testing strategies for the detection of Lynch syndrome. Data Sources.—This review is based on peer-reviewed literature, published guidelines from professional organizations (Evaluation of Genomic Applications in Practice and Prevention Working Group, National Comprehensive Cancer Network), and information from clinical laboratories performing microsatellite instability testing. Conclusions.—Universal screening for Lynch syndrome in all individuals affected with colorectal cancer has been recommended by the Evaluation of Genomic Applications in Practice and Prevention Working Group. Preliminary screening tests can identify individuals unlikely to be affected by Lynch syndrome, thereby reducing the need for full gene analysis. Immunohistochemistry and polymerase chain reaction–based tests for microsatellite instability have similar clinical sensitivity and specificity, and each method has advantages and limitations. BRAF and MLH1 methylation testing are useful reflex tests for those with a defect in MLH1 identified by immunohistochemistry. Emerging technologies, such as high-throughput sequencing, may substantially affect diagnostic algorithms in the future.

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Section: Members the Evaluation Of Genomic Applications Inmentioning

confidence: 99%

Microsatellite Instability and Colorectal Cancer

Geiersbach¹,

Samowitz²

2011

Archives of Pathology &Amp; Laboratory Medicine

121

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“…Since June 2008, the laboratory has used the MSI Analysis System from Promega (Madison, WI). 11 In Silico Analysis …”

Section: Microsatellite Instability Testingmentioning

confidence: 99%

The Germline MLH1 K618A Variant and Susceptibility to Lynch Syndrome-Associated Tumors

Medeiros

Lindor

Couch

et al. 2012

The Journal of Molecular Diagnostics

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Missense variants discovered during sequencing of cancer susceptibility genes can be problematic for clinical interpretation. MLH1 K618A, which results from a 2-bp alteration (AAG¡GCG) leading to a substitution of lysine to alanine in codon 618, has variously been interpreted as a pathogenic mutation, a variant of unknown significance, and a benign polymorphism. We evaluated the role of MLH1 K618A in predisposition to cancer by genotyping 1512 control subjects to assess its frequency in the general population. We also reviewed the literature concerning MLH1 K618A in families with colorectal cancer. The measured allele frequency of the K618A variant was 0.40%, which is remarkably close to the 0.44% summarized from 2491 control subjects in the literature. K618A was over-represented in families with suspected Lynch syndrome. In 1366 families, the allele frequency was 0.88% (OR ‫؍‬ 2.1, 95% CI ‫؍‬ 1.3 to 3.5; P ‫؍‬ 0.006). In studies of sporadic cancers of the type associated with Lynch syndrome, K618A was overrepresented in 1742 cases (allele frequency of 0.83) (OR ‫؍‬ 2.0, 95% CI ‫؍‬ 1.2 to 3.2; P ‫؍‬ 0.008). We conclude that MLH1 K618A is not a fully penetrant Lynch syndrome mutation, although it is not without effect, appearing to increase the risk of Lynch syndrome-associated tumors approximately twofold. Our systematic assessment approach may be useful for variants in other genes.

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“…NGS provides an unprecedented economy of scale, allowing dozens to hundreds of genes to be sequenced simultaneously for each patient and with higher sensitivity for low-prevalence mutations (16,17 ). Yet, because the majority of sporadic MSI-positive tumors often result from epigenetic changes rather than coding mutations in MMR genes (1,4 ), even fully sequencing all MMR pathway genes by NGS (18 ) will not provide sufficient data to reliably infer MSI status in a tumor. Alternatively, determination of epigenetic methylation patterns by NGS requires complex library preparation techniques (19 ), which also prevent the reliable detection of mutations.…”

mentioning

confidence: 99%