The Effects of Neoadjuvant Chemoradiation Therapy on Microsatellite Instability and Mismatch Repair Reporting in Rectal Adenocarcinoma.
Esther N Bit-Ivan, Jan A Nowak. NorthShore University HealthSystem, Evanston, IL; University of Chicago Pritzker School of Medicine, IL
Background: Mismatch repair protein expression and microsatellite instability (MSI) testing have become important tools in assessing patients with sporadic and inherited colorectal cancer (CRC). The predominant genes which affect DNA mismatch repair (MMR) include MLH1, MSH2, MSH6, and PMS2. MMR proteins form complexes that play an important role in maintaining fidelity during DNA replication and in recombinational repair. Their expression can be evaluated by the use of immunohistochemistry (IHC), while their function can be assessed by monitoring the stability of selected microsatellite loci.
Fifteen to 20% of all colorectal adenocarcinomas display defective MMR. The majority of deficient MMR is due to gene silencing by promoter hypermethylation (sporadic CRC). Approximately 2 to 5% of CRC are due to inherited mutations in the MMR genes, a manifestation of Lynch Syndrome, an autosomal dominant disorder which has clinical and prognostic implications.
The evaluation of tumors for MSI status and MMR expression is typically performed on excised specimens. Some patients, however, are treated with chemoradiation prior to surgery. Choi et al (Int J Radiat Oncol Biol Phys 68(5):1584 (2007)) recently reported that presurgical chemoradiation therapy can suppress or induce mismatch repair, potentially influencing the reliability of MSI and MMR evaluation performed on those specimens. The purpose of this study is to determine the effect of chemoradiation on MMR protein expression and MSI testing in CRC.
Design: Twenty patients with CRC who received presurgical chemoradiation between 7/05 and 7/10 were identified in our surgical pathology archives. Paraffin embedded pre-treatment and post-treatment samples were reviewed and evaluated to determine MSI status and MMR protein expression.
Results: Eighteen of 20 pre-treatment tumor specimens were classified as microsatellite stable (MSS) using a panel of five recommended mononucleotide microsatellite markers. One tumor exhibited instability in only one marker (MSI-L) and another tumor exhibited instability in two markers (MSI-H). All pre-treatment specimens demonstrated expression of the four MMR associated proteins by IHC analysis. Evaluation of postsurgical specimens showed no change in MSI status or expression of MMR proteins.
Conclusions: Our data do not support the hypothesis that neoadjuvant chemoradiation can change MMR status of tumors as determined by MSI testing or MMR protein expression.
Monday, February 28, 2011 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 216, Monday Morning