Sinicrope Frank A, Rego Rafaela L, Halling Kevin C, Foster Nathan R, Sargent Daniel J, La Plant Betsy, French Amy J, Allegra Carmen J, Laurie John A, Goldberg Richard M, Witzig Thomas E, Thibodeau Stephen N
Mayo Clinic and Mayo College of Medicine, Rochester, Minnesota 55905, USA.
Clin Cancer Res. 2006 May 1;12(9):2738-44. doi: 10.1158/1078-0432.CCR-06-0178.
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).
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.
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.
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.
高频微卫星不稳定（MSI-H）的结肠癌细胞对5-氟尿嘧啶（5-FU）具有抗性，而恢复DNA错配修复（MMR）功能可逆转这种抗性。鉴于胸苷酸合成酶（TS）受5-FU抑制，我们研究了MSI与TS表达之间的关系，以及这些指标和其他标志物（即p53和17p等位基因失衡）的预后影响。
对参加基于5-FU的辅助治疗试验的患者的 Dukes' B2期和C期结肠癌（n = 320）进行MSI和17p等位基因失衡分析。通过免疫组织化学分析MMR（hMLH1、hMSH2）、TS和p53蛋白的表达。确定标志物之间的相关性以及与总生存期的关联。
在研究的320例癌症中，60例（19%）为MSI-H。TS表达变量在MSI-H和微卫星稳定/低频MSI（MSS/MSI-L）癌症中相似，且与MMR蛋白无关。MSI-H肿瘤分期较低（P = 0.0007），转移淋巴结较少（P = 0.004），总生存期改善（P = 0.01）。MMR蛋白缺失也与较好的总生存期相关（P = 0.006）。TS的各项变量均无预后意义。组织学分级（P = 0.0008）和淋巴结状态（P = 0.0002）与总生存期相关，而17p等位基因失衡或p53则不然。只有MSI状态或MMR蛋白缺失、组织学分级和肿瘤分期是总生存期的独立标志物。
MSI-H肿瘤呈现出较早的分期和较好的分期调整生存率。MSI状态与TS表达无关，且TS无预后意义，这表明TS水平无法解释MSI-H结肠癌中报道的对5-FU的治疗抗性。
