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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
Summary
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.