[Microsatellite instability and therapeutic sensitivity].

Abstract

Based on the mechanism of their genetic instability human colorectal tumors can be subdived into two groups: (1) microsatellite stable (MSS) and (2) microsatellite instable (MSI-H) tumors. The reason for MSI-H is a defective mismatch repair (MMR) system. Besides the genetic mechanism MSI-H and MSS tumors differ also in other characteristics from each other. Mostly, MSI-H tumors are found in the proximal colon and display a moderate to weak differentiation. They display frequently a mucinous differentiation. MSI-H tumors harbour often tumor infiltrating lymphocytes (TIL) which are mostly of the CD8+ T-cell type. Moreover, MSI-H tumors display a higher frequency of apoptosis. But most importantly, patients with colorectal MSI-H tumors have a significant better prognosis compared to those with MSS tumors. Interestingly, cultured MSI-H colorectal cell lines are resistant to the adjuvant chemotherapeutical agent 5-fluorouracil (5FU) which is commonly used for the therapeutical treatment of colorectal cancers. The 5FU insensitivity is due to the defective MMR system which is responsible for the detection and repair of 5FU generated DNA helix-distorsions. Whereas 5FU has a strong impact on the survival of patients with MSS colorectal tumors, it is unclear if patients with MSI-H tumors benefit from adjuvant 5FU chemotherapy which is a conundrum as MSI-H cell lines are insensitive for this agent. Evidence is presented here, indicating that the results from studies demonstrating a benefit of MSI-H colorectal tumors from adjuvant 5FU chemotherapy are based on wrong statistical comparisons and that therefore patients with MSI-H colorectal tumors do not benefit from 5FU treatment.