The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer

// Dan Gao 1, 2 , James G. Herman 3 , Mingzhou Guo 1 1 Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China 2 Medical College of NanKai University, Tianjin, China 3 The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA Correspondence to: Mingzhou Guo, e-mail: mzguo@hotmail.com Keywords: DNA methylation, DNA damage repair, MGMT, synthetic lethality, PARP inhibitor Received: November 15, 2015     Accepted: February 20, 2016     Published: March 07, 2016 ABSTRACT 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.