Hereditary non-polyposis colorectal carcinoma (HNPCC), also known as Lynch Syndrome, is an autosomal dominant hereditary cancer syndrome associated with germline mutations in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6, and PMS2). As a consequence of these mutations, tumors from individuals with HNPCC/Lynch syndrome exhibit a phenomenon known as microsatellite instability (MSI). In addition, between 10 and 15 percent of sporadic colonic adenocarcinomas appear to display MSI, albeit via a different mechanism (e.g., CpG island methylation).
Microsatellites are repetitive sequences distributed throughout the genome that consist of single/multiple nucleotide repeats that are often copied incorrectly by DNA polymerase. In tumors with mismatch repair defects, these expansions or contractions in the number of nucleotide repeats are not repaired, leading to the phenomenon of MSI. PCR is used to amplify specific microsatellite repeats within the genome, and the number/length of the nucleotide repeats is compared in tumorcells versus normal cells. If the length of the repeat sequences from tumor versus normal differs, MSI is present.
This PCR based testing complements the immunohistochemistry-based assay also available at PhenoPath, in which the presence or loss of one of the MMR proteins is determined. While the IHC-based method detects loss of MMR protein expression, the PCR-based assay detects the end result of MMR dysfunction – MSI. While IHC can detect approximately >90% of the tumors with a defective MMR system, IHC may miss tumors containing mutations that produce a defective protein that is still expressed (i.e., missense mutations). Our new MSI PCR assay provides an additional tool to help clinicians and pathologists evaluate for HNPCC/Lynch Syndrome and the presence of MSI-type sporadic colorectal adenocarcinomas. Evaluation for MSI may also be useful in clinical decision-making, as sporadic colon cancers with MSI have a better prognosis compared to those with intact MMR systems, and appear to respond differently to adjuvant chemotherapy.