Association between mismatch repair gene and irinotecan-based chemotherapy in metastatic colon cancer
Mismatch repair (MMR) gene is closely related to the pathogenesis of colon cancer. This study aimed to evaluate the association between MMR status and efficacy of irinotecan-based chemotherapy. As a target of 5-FU, thymidylate synthase (TS) expression level might be influenced by irinotecan. Understanding whether this influence of TS is related with MMR status is helpful to the further exploration of the mechanism of irinotecan sensitivity in metastatic colon cancer with different MMR status. One hundred eighty-four patients with metastatic colon cancer receiving irinotecan-based chemotherapy for the first-line treatment were included. Correlations between MMR and clinicopathological characteristics and prognosis were determined. Two pairs of colon cancer cell lines (HCT-116-hMLH1Vector (deficient MMR, dMMR) versus HCT-116-hMLH1+ (proficient MMR, pMMR); SW480-shRNA-hMLH1 (dMMR) versus SW480-shRNA-Control (pMMR)) were established by regulating MMR status. Sensitivity of these cell lines to irinotecan was determined by MTT assay. Regulation of TS by irinotecan was evaluated by western blotting and quantitative real-time PCR assay. dMMR accounted for 18.5 % and was related with proximal colon cancer (p = 0.005), poorly differentiated tumors (p = 0.018) and favorable efficacy with a higher disease control rate (DCR), a longer progression-free survival (PFS) and a trend of longer overall survival (OS). dMMR colon cancer cells were more sensitive to irinotecan. TS expression level was reduced more in dMMR cells after irinotecan treatment (p < 0.05). Our study favors an increased sensitivity of irinotecan in colon cancer with dMMR status. MMR status may be a predictive biomarker of response to irinotecan-based chemotherapy in metastatic colon cancer.
KeywordsColon cancer Mismatch repair gene Irinotecan 5-Fluorouracil Thymidylate synthase
This study was supported by the grants from the National Nature Science Foundation of China (nos. 30770971, 81172470, 81070362, and 81372629).
Compliance with ethical standards
The manuscript has been performed with the approval of the ethics of Xiangya Hospital, Central South University. Informed consent was obtained from all the patients before enrollment in the study. This study was prospectively performed and approved by the institutional Ethics Committees of our hospital and conducted in accordance with the ethical guidelines of the Declaration of Helsinki.
Conflict of interest
The authors declare that they have no competing interests.
- 11.Juo YY, Johnston FM, Zhang DY, Juo HH, Wang H, et al. Prognostic value of CpG island methylator phenotype among colorectal cancer patients: a systematic review and meta-analysis. Ann Oncol. 2014;25:2314–27.Google Scholar
- 15.Bertagnolli MM, Niedzwiecki D, Compton CC, Hahn HP, Hall M, et al. Microsatellite instability predicts improved response to adjuvant therapy with irinotecan, fluorouracil, and leucovorin in stage III colon cancer: Cancer and Leukemia Group B Protocol 89803. J Clin Oncol. 2009;27:1814–21.CrossRefPubMedPubMedCentralGoogle Scholar