Institute of Experimental Medicine, and Institute of Biotechnology, Academy of Sciences, Czech Republic.
Clin Cancer Res. 2012 Nov 1;18(21):5878-87. doi: 10.1158/1078-0432.CCR-12-1380. Epub 2012 Sep 10.
DNA repair capacity (DRC) is a determinant not only of cancer development but also of individual response to therapy. Previously, altered base and nucleotide excision repair (BER and NER) have been described in lymphocytes of patients with sporadic colorectal cancer. We, for the first time, evaluate both excision repair capacities in human colon biopsies to study their participation in colorectal tumorigenesis.
Seventy pairs of tumor and adjacent healthy tissues were analyzed for BER- and NER-specific DRC by a comet repair assay. Tissue pairs were further compared for expression levels of a panel of 25 BER and NER genes complemented by their promoter methylation status.
We observed a moderate increase of NER-DRC (P = 0.019), but not of BER-DRC in tumors. There was a strong correlation between both tissues for all investigated parameters (P < 0.001). However, 4 NER (CSB, CCNH, XPA, XPD) and 4 BER (NEIL1, APEX1, OGG1, PARP1) genes showed a 1.08- to 1.28-fold change difference in expression in tumors (P < 0.05). Individual gene expression levels did not correlate with overall DRC, and we did not detect any aberrant methylation of the investigated genes.
Our complex analysis showed that tumor cells are not deficient in BER and NER, but rather follow patterns characteristic for each individual and are comparable with adjacent tissue. Alteration of excision repair pathways is not a pronounced event in colorectal carcinogenesis. This study shows the feasibility of DRC evaluation in human solid tissues, representing a complex marker of multigene DNA repair processes.
DNA 修复能力（DRC）不仅是癌症发展的决定因素，也是个体对治疗反应的决定因素。先前已经描述了散发性结直肠癌患者淋巴细胞中的碱基和核苷酸切除修复（BER 和 NER）改变。我们首次评估了人类结肠活检中的两种切除修复能力，以研究它们在结直肠肿瘤发生中的作用。
通过彗星修复试验分析了 70 对肿瘤和相邻正常组织的 BER 和 NER 特异性 DRC。进一步比较组织对 25 个 BER 和 NER 基因的表达水平及其启动子甲基化状态。
我们观察到 NER-DRC 中度增加（P = 0.019），但肿瘤中 BER-DRC 没有增加。所有研究参数的两种组织之间均存在很强的相关性（P < 0.001）。然而，在肿瘤中，有 4 个 NER（CSB、CCNH、XPA、XPD）和 4 个 BER（NEIL1、APEX1、OGG1、PARP1）基因的表达水平差异为 1.08-1.28 倍（P < 0.05）。个体基因表达水平与总体 DRC 不相关，并且我们没有检测到所研究基因的异常甲基化。
我们的综合分析表明，肿瘤细胞在 BER 和 NER 中没有缺陷，而是遵循每个个体的特征模式，与相邻组织相当。切除修复途径的改变不是结直肠癌变中的一个明显事件。这项研究表明了在人体实体组织中评估 DRC 的可行性，它代表了多基因 DNA 修复过程的复杂标志物。
