Department of Medical Genetics, Third Faculty of Medicine, Charles University, Ruska 2411/87, 100 00, Prague, Czech Republic; Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Albertov 4, 128 00, Prague, Czech Republic.
Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 142 20 Prague, Czech Republic; Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in Prague, Albertov 4, 128 00, Prague, Czech Republic.
DNA Repair (Amst). 2018 Dec;72:77-85. doi: 10.1016/j.dnarep.2018.09.006. Epub 2018 Oct 1.
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.
DNA 损伤剂 5-氟尿嘧啶是结直肠癌患者最常用的化疗药物。与 5-氟尿嘧啶治疗相关的 DNA 损伤主要通过碱基切除修复 (BER) 和错配修复 (MMR) 途径修复。已发表的证据表明，个体 DNA 修复能力 (DRC) 可能影响患者的预后和对化疗的反应。考虑到这一点，我们设计了一项前瞻性研究，其主要目的是研究 BER-DRC 与 5-氟尿嘧啶反应的关系，作为潜在的预测和/或预后生物标志物。BER-DRC 通过微卫星不稳定性 (MSI) 分析得到补充，MSI 分析是肿瘤中 MMR 活性的间接标志物。所有参数均在 123 例新发结肠癌患者的肿瘤组织和非恶性相邻粘膜的配对样本中进行测量。我们的研究结果表明，非恶性相邻粘膜中的 BER-DRC 与总生存 (P=0.007) 和无复发生存 (P=0.04) 呈正相关。此外，在多变量分析中，TNM 分期 II 和 III 期的良好治疗反应者，其粘膜中 BER-DRC 升高，总生存情况更好。此外，这些患者的总生存情况甚至在肿瘤组织中 BER-DRC 降低的情况下更好。肿瘤组织中 BER-DRC 与粘膜中 BER-DRC 的比值与晚期肿瘤分期呈正相关 (P=0.003)。关于 MSI，我们观察到 MSI-高肿瘤主要位于近端结肠；然而，在我们的队列中，MSI 状态既不影响患者的预后，也不影响生存。总之，本研究的结果表明，BER-DRC 水平与患者的生存有关。BER-DRC 是一种潜在的预后生物标志物，可用于预测治疗反应，并有助于对患者进行个体化治疗。
