Gao Dan, Herman James G, Guo Mingzhou
Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China.
Medical College of NanKai University, Tianjin, China.
Oncotarget. 2016 Jun 14;7(24):37331-37346. doi: 10.18632/oncotarget.7949.
The stability and integrity of the human genome are maintained by the DNA damage repair (DDR) system. Unrepaired DNA damage is a major source of potentially mutagenic lesions that drive carcinogenesis. In addition to gene mutation, DNA methylation occurs more frequently in DDR genes in human cancer. Thus, DNA methylation may play more important roles in DNA damage repair genes to drive carcinogenesis. Aberrant methylation patterns in DNA damage repair genes may serve as predictive, diagnostic, prognostic and chemosensitive markers of human cancer. MGMT methylation is a marker for poor prognosis in human glioma, while, MGMT methylation is a sensitive marker of glioma cells to alkylating agents. Aberrant epigenetic changes in DNA damage repair genes may serve as therapeutic targets. Treatment of MLH1-methylated colon cancer cell lines with the demethylating agent 5'-aza-2'-deoxycytidine induces the expression of MLH1 and sensitizes cancer cells to 5-fluorouracil. Synthetic lethality is a more exciting approach in patients with DDR defects. PARP inhibitors are the most effective anticancer reagents in BRCA-deficient cancer cells.
人类基因组的稳定性和完整性由DNA损伤修复（DDR）系统维持。未修复的DNA损伤是驱动致癌作用的潜在诱变损伤的主要来源。除了基因突变外，DNA甲基化在人类癌症的DDR基因中更频繁地发生。因此，DNA甲基化可能在DNA损伤修复基因中发挥更重要的作用以驱动致癌作用。DNA损伤修复基因中的异常甲基化模式可能作为人类癌症的预测、诊断、预后和化学敏感性标志物。MGMT甲基化是人类胶质瘤预后不良的标志物，而MGMT甲基化是胶质瘤细胞对烷化剂敏感的标志物。DNA损伤修复基因中的异常表观遗传变化可能作为治疗靶点。用去甲基化剂5'-氮杂-2'-脱氧胞苷处理MLH1甲基化的结肠癌细胞系可诱导MLH1的表达并使癌细胞对5-氟尿嘧啶敏感。合成致死性是DDR缺陷患者中一种更令人兴奋的方法。PARP抑制剂是BRCA缺陷癌细胞中最有效的抗癌试剂。
