Clinical Uses of Microsatellite Instability Testing in Colorectal Cancer: An Ongoing Challenge

Microsatellite instability (MSI) is the mutational signature found in colorectal cancers (CRCs) that evolve as a result of inactivation of the DNA mismatch repair (MMR) system.MSI can be found in approximately 15% of all CRCs.Approximately 3% of all CRCs are a consequence of Lynch Syndrome, and nearly all Lynch Syndrome CRCs have MSI. 1 Another 12% of CRCs represent the noninherited form of DNA MMR inactivation that is induced by methylation of the promoter of the MLH1 gene, which silences gene expression. 2MSI is one of the premier molecular markers in CRC because it indicates the pathophysiologic genesis of the tumor, and it provides some clinical information that is of use in caring for this subset of CRC patients.Testing for MSI is within the grasp of a molecular diagnostic laboratory, and many investigators have proposed various clinical applications of this information.This issue of the Journal of Clinical Oncology includes two articles on testing the clinical utility of MSI 3,4 ; one of which confirms its utility in identifying Lynch Syndrome families, 3 the other casts doubt on its utility as a prognostic and predictive marker in sporadic CRC. 4 These articles illustrate the utility of molecular diagnostics, but also note the challenges of using new technologies.Valle and colleagues 3 gathered 64 familial clusters of CRC from a Spanish national registry, all of whom met the Amsterdam-I criteria. 5Each family had a pedigree that included at least three members with CRC, and at least one affected member was younger than 50 years old.This was the classic algorithm to identify Lynch Syndrome families, and it was initially assumed to be very specific for this diagnosis.However, a registry of familial clusters of CRC (the Colon Cancer Family Registry, or Colon CFR) reported that only Ϸ60% of these classic clusters can be linked to a germline mutation in a DNA MMR gene.The other 40% of families had microsatellite stable (MSS) tumors, and these families have been given the temporary designation "Syndrome X"; the genetic basis of this syndrome is being explored. 6Valle et al 3 found that virtually the same proportion of the Spanish families had MSI CRCs (59.4%), a highly reassuring confirmation of the data from the Colon CFR.Her group was able to find the responsible germline mutation in 65.7% of these families, which is critical for clinical care, because this permits accurate case finding and genetic counseling.Moreover, they confirmed that true Lynch Syndrome families developed their cancers earlier in life (mean age 45.5 years v 53 years for families with MSS tumors), that 70.6% of the CRCs were proximally located in the MSI families, and that the tumor spec-