Prospective Evaluation of Mismatch Repair Protein Expression in Primary Colorectal Cancer

Abstract

Purpose: Immunohistochemical (IHC) stains for mismatch repair (MMR) proteins identify microsatellite unstable colorectal cancer (CRC) and help screen for Lynch Syndrome (LS). It has been suggested that CRC should be screened routinely for a MMR defect, but data are lacking on the practical application of this policy. We report our experience with the prospective evaluation of MMR protein expression in CRC. Methods: All cases of primary CRC at a single institution were prospectively stained for the MMR proteins MLH1, MSH2, MSH6, and PMS2. Cases from outside institutions, biopsies, or metastatic resections were excluded. The stains were read by a GI pathologist and reported as absent or present protein expression. If a tumor exhibited absence of a MMR protein, the Genetics Program was informed. A genetic counselor then attempted to contact the patient to review the IHC result and offer consultation. Further testing was performed based on indication and patient preference with informed consent. Results: From March 1, 2006 through October 31, 2007, 227 cases of primary CRC were diagnosed at our institution. Of these 16.3% (37/227) stained absent for one or two MMR proteins. All 37 individuals whose tumor stained absent for MMR proteins were successfully contacted by the clinical cancer genetics program. Of these 37 individuals 12 (32.4%) made an appointment with the clinical cancer genetics department. Six patients attended their appointment (6 cancelled). Five individuals underwent further genetic testing. One individual was found to have methylation of the MLH1 promoter. One was found to have a deleterious germline mutation of the MLH1 gene and one was found to have a deleterious germline mutation of the MSH6 gene. Reimbursement was obtained at a level similar to other IHC stains used in clinical practice. Conclusion: IHC staining for MMR proteins is relatively easy to institute in the routine evaluation of CRC, does not lead to substantial additional testing, and is reimbursed at levels similar to other IHC stains. Furthermore, most patients are interested in testing and are willing to accept genetic counseling. Finally, a significant number of individuals can be identified with LS potentially leading to the early referral of at risk family members for high risk CRC screening/surveillance.