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

Abstract

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.

• Authors: Junli Ma, Yan Zhang, Hong Shen, Linda Kapesa, Wenqiang Liu, Mengsi Zeng, Shan Zeng
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 36 Issue 12 Pg. 9599-609 (Dec 2015) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 26142736 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

• Adaptor Proteins, Signal Transducing (biosynthesis, genetics)
• Aged
• Camptothecin (administration & dosage, analogs & derivatives)
• Colonic Neoplasms (drug therapy, genetics, 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, genetics)
• Nuclear Proteins (biosynthesis, genetics)
• Prognosis
• Thymidylate Synthase (biosynthesis, genetics)
• Treatment Outcome