title: The clinical value of aberrant epigenetic changes of DNA damage repair genes in human cancer.
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.
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China.|Medical College of NanKai University, Tianjin, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Gao
authors.affiliation: The Hillman Cancer Center, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Herman
authors.affiliation: Department of Gastroenterology and Hepatology, Chinese PLA General Hospital, Beijing, China.
authors.forename: Mingzhou
authors.initials: M
authors.lastname: Guo
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D001374:Azacitidine / Q000031:analogs & derivatives / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D004249:DNA Damage; D019175:DNA Methylation / Q000235:genetics*; D015254:DNA Modification Methylases / Q000235:genetics*; D004260:DNA Repair / Q000235:genetics*; D045643:DNA Repair Enzymes / Q000235:genetics*; D000077209:Decitabine; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D044127:Epigenesis, Genetic; D005472:Fluorouracil / Q000627:therapeutic use; D006801:Humans; D058990:Molecular Targeted Therapy / Q000401:mortality; D009369:Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000401:mortality; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D000964:Antimetabolites, Antineoplastic; D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D000077209:Decitabine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D001374:Azacitidine; D005472:Fluorouracil
keywords: DNA damage repair; DNA methylation; MGMT; PARP inhibitor; synthetic lethality