title: Thymidylate synthase expression in colon carcinomas with microsatellite instability.
abstract: OBJECTIVE
  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).
  
  
  METHODS
  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.
authors: Mayo Clinic and Mayo College of Medicine, Rochester, Minnesota 55905, USA. sinicrope.frank@mayo.edu
authors: Frank A
authors: FA
authors: Sinicrope
authors: Rafaela L
authors: RL
authors: Rego
authors: Kevin C
authors: KC
authors: Halling
authors: Nathan R
authors: NR
authors: Foster
authors: Daniel J
authors: DJ
authors: Sargent
authors: Betsy
authors: B
authors: La Plant
authors: Amy J
authors: AJ
authors: French
authors: Carmen J
authors: CJ
authors: Allegra
authors: John A
authors: JA
authors: Laurie
authors: Richard M
authors: RM
authors: Goldberg
authors: Thomas E
authors: TE
authors: Witzig
authors: Stephen N
authors: SN
authors: Thibodeau