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

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          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.

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          Mechanisms and functions of DNA mismatch repair.

          Guo-Min Li (2008)
          DNA mismatch repair (MMR) is a highly conserved biological pathway that plays a key role in maintaining genomic stability. The specificity of MMR is primarily for base-base mismatches and insertion/deletion mispairs generated during DNA replication and recombination. MMR also suppresses homeologous recombination and was recently shown to play a role in DNA damage signaling in eukaryotic cells. Escherichia coli MutS and MutL and their eukaryotic homologs, MutSalpha and MutLalpha, respectively, are key players in MMR-associated genome maintenance. Many other protein components that participate in various DNA metabolic pathways, such as PCNA and RPA, are also essential for MMR. Defects in MMR are associated with genome-wide instability, predisposition to certain types of cancer including hereditary non-polyposis colorectal cancer, resistance to certain chemotherapeutic agents, and abnormalities in meiosis and sterility in mammalian systems.
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            Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability.

            Asad Umar, C. Boland, Jonathan Terdiman … (2004)
            Hereditary nonpolyposis colorectal cancer (HNPCC), also known as Lynch syndrome, is a common autosomal dominant syndrome characterized by early age at onset, neoplastic lesions, and microsatellite instability (MSI). Because cancers with MSI account for approximately 15% of all colorectal cancers and because of the need for a better understanding of the clinical and histologic manifestations of HNPCC, the National Cancer Institute hosted an international workshop on HNPCC in 1996, which led to the development of the Bethesda Guidelines for the identification of individuals with HNPCC who should be tested for MSI. To consider revision and improvement of the Bethesda Guidelines, another HNPCC workshop was held at the National Cancer Institute in Bethesda, MD, in 2002. In this commentary, we summarize the Workshop presentations on HNPCC and MSI testing; present the issues relating to the performance, sensitivity, and specificity of the Bethesda Guidelines; outline the revised Bethesda Guidelines for identifying individuals at risk for HNPCC; and recommend criteria for MSI testing.
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              Platinum resistance: the role of DNA repair pathways.

              Lainie Martin, Thomas Hamilton, Russell J Schilder (2008)
              Although platinum chemotherapeutic agents such as carboplatin, cisplatin, and oxaliplatin are used to treat a broad range of malignant diseases, their efficacy in most cancers is limited by the development of resistance. There are multiple factors that contribute to platinum resistance but alterations of DNA repair processes have been known for some time to be important in mediating resistance. Recently acquired knowledge has provided insight into the molecular mechanisms of DNA repair pathways and their effect on response to chemotherapy. This review will discuss the most important DNA repair pathways known to be involved in the platinum response, i.e., nucleotide excision repair (NER) and mismatch repair (MMR), and will briefly touch on the role of BRCA in DNA repair. The therapeutic implications of alterations in DNA repair which affect response to platinum in the treatment of patients with malignant disease, such as excision repair cross-complementation group 1 (ERCC1) deficiency and mismatch repair deficiency, will be reviewed.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 14 June 2016
                Publication date (Electronic): 7 March 2016
                Volume: 7
                Issue: 24
                Pages: 37331-37346
                Affiliations
                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
                Author notes
                Correspondence to: Mingzhou Guo, mzguo@ 123456hotmail.com
                Article
                Publisher ID: 7949
                DOI: 10.18632/oncotarget.7949
                PMC ID: 5095080
                PubMed ID: 26967246
                SO-VID: 560a4210-37c7-4981-89a1-f398eaa273fe
                Copyright © Copyright: © 2016 Gao et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 15 November 2015
                Date accepted : 20 February 2016
                Categories
                Subject: Review

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: dna methylation,dna damage repair,mgmt,synthetic lethality,parp inhibitor
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: dna methylation, dna damage repair, mgmt, synthetic lethality, parp inhibitor

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