Relationship between Microsatellite Instability and Dihydropyrimidine Dehydrogenase Expression as a Predictor of Response to 5-Fluorouracil Chemotherapy for Colorectal Cancer

ABSTRACT

PURPOSE: Dihydropyrimidine dehydrogenase (DPD) is a rate-limiting enzyme in 5-FU catabolism, so the enzymatic activity of DPD reflects the 5-FU response. Moreover, recent studies have revealed that microsatellite instability (MSI) status correlates well with the prognosis and the 5-FU chemosensitivity in colorectal cancer (CRC). This study aimed to determine whether DPD mRNA expression is related with the MSI status of primary CRC as a prognostic predictor. METHODS: Tumor samples and adjacent normal colonic mucosal tissues were collected from 59 patients. DPD mRNA expression was calculated by using the real-time RT-PCR method. The MSI status was examined by using multiplex fluorescent PCR with five reference markers. The results of DPD mRNA expression and MSI status were compared with the clinicopathologic variables and with each other. RESULTS: The mean age of the 59 patients was 59 (range 36~81) years. In 55 patients (93.2%), the colorectal cancers were histologically well or moderately differentiated. Forty-nine of the tumors (49, 83.1%) were located distal to the splenic flexure, and 46 patients (78%) had TNM stage II (n=17) or stage III (n=29) cancer. The DPD mRNA expression level was informative in all 59 cases. The median expression level was 2.5 (range 0~67.33). There was no correlation between the DPD mRNA expression level and age, gender, location, or TNM stage. MSI status was informative in 43 cases (72.9%). Thirty-six cases (36, 83.7%) were microsatellite-stable (MSS), 4 cases (9.3%) showed low-level microsatellite instability (MSI-L), and 3 cases (7.0%) showed high-level microsatellite instability (MSI-H). Proximal CRC showed a higher proportion of MSI-H than distal CRC (25% vs. 2.9%, P=0.03). We could not find any correlation between the DPD mRNA expression level and the MSI status in tumor tissues (r=0.29, P=0.09). CONCLUSIONS: The expression level of DPD mRNA raried among the tumors studied. The relatively low frequency of MSI in distal CRC prohibits the use of MSI status as a predictor of 5-FU chemosensitivity. We suggest that a well-designed large-scale study would be helpful to confirm the relation between DPD mRNA expression and MSI status as a predictor of 5-FU chemosensitivity in CRC patients.