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. 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. MSI 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; one of which confirms its utility in identifying Lynch Syndrome families, the other casts doubt on its utility as a prognostic and predictive marker in sporadic CRC. These articles illustrate the utility of molecular diagnostics, but also note the challenges of using new technologies. Valle and colleagues gathered 64 familial clusters of CRC from a Spanish national registry, all of whom met the Amsterdam-I criteria. Each 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 60% 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. Valle et al 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 spectrum was of the Lynch Syndrome variety in the MSI families, whereas CRC was frequently the sole cancer in the MSS families. This work confirms the utility of MSI testing to accurately classify familial clusters of CRC. Kim and colleagues examined the two other clinical uses of MSI testing in CRC: its value in predicting prognosis, and the response to chemotherapy. This group used the potentially risky approach of mining data retrospectively from prior National Surgical Adjuvant Breast and Bowel Project (NSABP) Collaborative Studies (trials C-01 through C-04), an approach necessitated by the absence of control groups that were not treated with chemotherapy since the late 1980s. The nature of this retrospective study required using untreated controls from trials C-01 and C-02, and compared them with treated patients from trials C-03 and C-04 —an approach that statisticians prefer to avoid. Patient selection, diagnostic and staging techniques, and other unknown variables, all change over time. Tissue blocks were available for only 20% of untreated patients, adding sampling issues to this complex analysis. Unlike using MSI to test for Lynch Syndrome, clinical predictive applications of MSI testing have been more controversial. It was noted in the initial discovery of MSI in CRC that patients with MSI tumors had better rates of survival. This has been confirmed by others, particularly in younger patients (in whom the difference is especially impressive), but other reports have had mixed findings. This may be due, at least in part, to the fact that the age distribution of MSI CRC patients is bimodal. Lynch Syndrome patients make up 20% to 25% of the MSI group, and develop CRC at an average age in the mid-40s. The sporadic, methylation-related MSI-CRC patients make up the other 75% to 80%, and are typically older than other sporadic CRC patients, with an average age that is older than 70 years. Depending on the relative proportions of each, one might get a cohort with many comorbidities, on the one hand, or a young, healthier group on the other. Kim et al found an interesting reduction in tumor recurrence for the MSI group (relative risk 0.68), which was not significant because of the wide confidence intervals. The relative risk for overall survival was modest at best (relative risk 0.91 for MSI tumors). Because many tissue specimens were unavailable for analysis, the number of patients analyzed was relatively small, inviting the possibility of missing a significant association through a beta error. However, to JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 25 NUMBER 7 MARCH 1 2007