Association between mismatch repair gene and irinotecan-based chemotherapy in metastatic colon cancer

Tumour Biol. 2015 Dec;36(12):9599-609. doi: 10.1007/s13277-015-3723-5. Epub 2015 Jul 5.


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-hMLH1(Vector) (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.

Keywords: 5-Fluorouracil; Colon cancer; Irinotecan; Mismatch repair gene; Thymidylate synthase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / biosynthesis
  • Adaptor Proteins, Signal Transducing / genetics
  • Aged
  • Camptothecin / administration & dosage
  • Camptothecin / analogs & derivatives*
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics
  • Colonic Neoplasms / pathology
  • DNA Mismatch Repair / genetics*
  • Disease-Free Survival
  • Female
  • Fluorouracil / administration & dosage
  • Gene Expression Regulation, Neoplastic / drug effects
  • HCT116 Cells
  • Humans
  • Irinotecan
  • Male
  • Middle Aged
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein / biosynthesis
  • MutS Homolog 2 Protein / genetics
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics
  • Prognosis
  • Thymidylate Synthase / biosynthesis*
  • Thymidylate Synthase / genetics
  • Treatment Outcome


  • Adaptor Proteins, Signal Transducing
  • MLH1 protein, human
  • Nuclear Proteins
  • Irinotecan
  • Thymidylate Synthase
  • MSH2 protein, human
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Fluorouracil
  • Camptothecin