Base excision repair capacity as a determinant of prognosis and therapy response in colon cancer patients

DNA Repair (Amst). 2018 Dec:72:77-85. doi: 10.1016/j.dnarep.2018.09.006. Epub 2018 Oct 1.

Abstract

The DNA-damaging agent 5-fluorouracil represents the most commonly used chemotherapeutic drug for colorectal cancer patients. DNA lesions associated with 5-fluorouracil therapy are primarily repaired by base excision repair (BER) and mismatch repair (MMR) pathways. Published evidence suggests that the individual DNA repair capacity (DRC) may affect a patient's prognosis and response to chemotherapy. With this in mind, we designed a prospective study of which the main aim was to investigate BER-DRC in relation to 5-fluorouracil response as potential predictive and/or prognostic biomarker. BER-DRC was supplemented by a microsatellite instability (MSI) analysis which represents an indirect marker of MMR activity in the tumor. All parameters were measured in paired samples of tumor tissue and non-malignant adjacent mucosa of 123 incident colon cancer patients. Our results indicate that BER-DRC in non-malignant adjacent mucosa was positively associated with overall survival (P = 0.007) and relapse-free survival (P = 0.04). Additionally, in multivariate analysis, good therapy responders in TNM stage II and III with an elevated BER-DRC in mucosa exhibited better overall survival. Moreover, the overall survival of these patients was even better in the presence of a decreased BER-DRC in tumor tissue. The ratio of BER-DRC in tumor tissue over BER-DRC in mucosa positively correlated with advanced tumor stage (P = 0.003). With respect to MSI, we observed that MSI-high tumors were mostly localized in proximal colon; however, in our cohort, the MSI status affected neither patients' prognosis nor survival. In summary, the results of the present study suggest that the level of BER-DRC is associated with patients' survival. BER-DRC represents a potential prognostic biomarker, applicable for prediction of therapy response and useful for individual approach to patients.

Keywords: 5-Fluorouracil; Base excision repair; Colon cancer; Microsatellite instability; Patient survival; Therapy response.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Colonic Neoplasms / diagnosis
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / genetics*
  • DNA Repair / drug effects*
  • Female
  • Humans
  • Male
  • Microsatellite Instability / drug effects
  • Middle Aged
  • Prognosis
  • Survival Analysis
  • Treatment Outcome