The Case for Laboratory Developed Procedures: Quality and Positive Impact on Patient Care

Kaul, Karen L.; Sabatini, Linda M.; Tsongalis, Gregory J.; Caliendo, Angela M.; Olsen, Randall J.; Ashwood, Edward R.; Bale, Sherri; Benirschke, Robert; Carlow, Dean; Funke, Birgit H.; Grody, Wayne W.; Hayden, Randall T.; Hegde, Madhuri; Lyon, Elaine; Murata, Kazunori; Pessin, Melissa; Press, Richard D.; Thomson, Richard B.

Microsatellite instability is the presence of hypermutability in repetitive DNA sequences resulting from impaired DNA mismatch repair. Microsatellite instability can be an inherited or acquired feature of tumors. Microsatellite instability occurs in approximately 15% of all colorectal carcinomas and is a consistent feature of colorectal and other tumors in patients with Lynch syndrome. 64 Tumors are classified as showing high levels of MSI (MSI-H phenotype) if 2 or more of 5 microsatellite markers (or !30%) exhibit instability, a microsatellite-stable phenotype if none of the markers show instability, and an MSIlow phenotype if only 1 of 5 or less than 30% of the markers show instability. 65 Studies have confirmed that the appropriate cutoff for determining an MSI-H phenotype is the finding of instability in 30% or more of the markers tested. The finding of an MSI-H phenotype is consistent with the presence of defective DNA MMR in the tumor. 66 The finding of an MSI-H phenotype in a CRC increases the likelihood that the patient has LS but is not specific for LS. The definitive establishment of a diagnosis of LS requires the finding of a pathogenic germline mutation in one of the DNA MMR genes. Additional testing that can be offered to determine whether a patient with an MSI-H CRC is likely to have LS includes testing the tumor for DNA MMR protein expression using IHC, BRAF V600E point mutation analysis (since BRAF-mutated MSI-H colorectal carcinomas are known to have sporadic MMR gene mutations), and MLH1 promoter hypermethylation.