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Published on: July 28, 2010
Thymidylate synthase expression in colon carcinomas with microsatellite instability
Frank A Sinicrope1, Rafaela L Rego, Kevin C Halling
1Mayo Clinic and Mayo College of Medicine, Rochester, Minnesota 55905, USA. sinicrope.frank@mayo.edu
Purpose:
Colon cancer cells with high-frequency microsatellite instability (MSI-H) display resistance to 5-fluorouracil (5-FU) that can be reversed by restoring DNA mismatch repair (MMR) proficiency. Given that thymidylate synthase (TS) is inhibited by 5-FU, we studied the relationship between MSI and TS expression, and the prognostic effect of these and other markers (i.e., p53 and 17p allelic imbalance).
Experimental Design:
Dukes' stage B2 and C colon carcinomas (n = 320) from participants in 5-FU-based adjuvant therapy trials were analyzed for MSI and 17p allelic imbalance. Expression of MMR (hMLH1, hMSH2), TS, and p53 proteins were analyzed by immunohistochemistry. Correlations between markers and associations with overall survival were determined.
Results:
Of 320 cancers studied, 60 (19%) were MSI-H. TS expression variables were similar in MSI-H and microsatellite stable/low-frequency MSI (MSS/MSI-L) cancers, and unrelated to MMR proteins. MSI-H tumors had lower stage (P = 0.0007), fewer metastatic lymph nodes (P = 0.004), and improved overall survival (P = 0.01). Loss of MMR proteins was also associated with better overall survival (P = 0.006). None of the TS variables were prognostic. Histologic grade (P = 0.0008) and nodal status (P = 0.0002) were associated with overall survival, in contrast to 17p allelic imbalance or p53. Only MSI status or loss of MMR proteins, histologic grade, and tumor stage were independent markers for overall survival.
Conclusions:
MSI-H tumors show earlier stage at presentation and better stage-adjusted survival rates. MSI status and TS expression were unrelated and TS was not prognostic, suggesting that TS levels cannot explain therapeutic resistance to 5-FU reported in MSI-H colon cancers.
Insights
High-frequency microsatellite instability (MSI-H) colon cancers present at earlier stages and have better survival rates. Thymidylate synthase (TS) expression does not explain the resistance of MSI-H tumors to 5-fluorouracil (5-FU).
Area of Science:
- Oncology
- Molecular Biology
- Cancer Genetics
Background:
- Colon cancer exhibits varying responses to 5-fluorouracil (5-FU) chemotherapy.
- High-frequency microsatellite instability (MSI-H) is linked to 5-FU resistance, potentially due to altered DNA mismatch repair (MMR) or thymidylate synthase (TS) expression.
Purpose of the Study:
- To investigate the relationship between MSI status and TS expression in colon cancer.
- To evaluate the prognostic significance of MSI, TS, p53, and 17p allelic imbalance in colon carcinomas treated with 5-FU.
Main Methods:
- Analysis of 320 Dukes' stage B2 and C colon carcinomas from 5-FU adjuvant therapy trials.
- Assessment of microsatellite instability (MSI), 17p allelic imbalance, and expression of MMR proteins (hMLH1, hMSH2), TS, and p53 via immunohistochemistry.
Main Results:
- MSI-H (19%) tumors were associated with earlier stage, fewer positive lymph nodes, and improved overall survival.
- TS expression was similar in MSI-H and microsatellite stable/low-frequency MSI (MSS/MSI-L) tumors and not prognostic.
- Loss of MMR proteins also correlated with better survival; only MSI status, MMR protein loss, histologic grade, and tumor stage were independent prognostic markers.
Conclusions:
- MSI-H colon tumors present at an earlier stage and have better survival rates.
- TS expression is unrelated to MSI status and does not predict prognosis.
- TS levels do not account for the observed 5-FU resistance in MSI-H colon cancers.
