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

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.

[1]  H. Neamatzadeh,et al.  BRCA1 and BRCA2 mutations in Iranian breast cancer patients: A systematic review , 2015, Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences.

[2]  Scar,et al.  Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. , 2000, The New England journal of medicine.

[3]  Matej Horvat,et al.  Microsatellite instability in colorectal cancer , 2011, Radiology and oncology.

[4]  H. Koeffler,et al.  Methylation of the MLH1 gene in hematological malignancies. , 2005, Oncology reports.

[5]  Gary L Rosner,et al.  Tumour vasculature: On the verge of collapse , 2005, Nature Reviews Cancer.

[6]  Rahul Bhagat,et al.  Microsatellite instability, promoter methylation and protein expression of the DNA mismatch repair genes in epithelial ovarian cancer. , 2014, Genomics.

[7]  E. Swisher,et al.  Secondary mutations of BRCA1/2 and drug resistance , 2011, Cancer science.

[8]  L. Aaltonen,et al.  The role of hypermethylation of thehMLH1 promoter region in HNPCC versus MSI+ sporadic colorectal cancers , 2000, Journal of medical genetics.

[9]  J. Herman,et al.  Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Min Wu,et al.  Mutations of O6‐methylguanine‐DNA methyltransferase gene in esophageal cancer tissues from Northern China , 1997, International journal of cancer.

[11]  S. Leung,et al.  Heritable germline epimutation of MSH2 in a family with hereditary nonpolyposis colorectal cancer , 2006, Nature Genetics.

[12]  Tongyu Zhu,et al.  A Novel Set of DNA Methylation Markers in Urine Sediments for Sensitive/Specific Detection of Bladder Cancer , 2007, Clinical Cancer Research.

[13]  A. Ashworth,et al.  Therapeutic Targeting of the DNA Mismatch Repair Pathway , 2010, Clinical Cancer Research.

[14]  Y. Ling,et al.  The effects of ERCC1 expression levels on the chemosensitivity of gastric cancer cells to platinum agents and survival in gastric cancer patients treated with oxaliplatin-based adjuvant chemotherapy , 2012, Oncology letters.

[15]  A. D’Andrea.  The Fanconi Anemia/BRCA Signaling Pathway: Disruption in Cisplatin-Sensitive Ovarian Cancers , 2003, Cell cycle.

[16]  R. Hruban,et al.  Fanconi anemia gene mutations in young-onset pancreatic cancer. , 2003, Cancer research.

[17]  J. Bartek,et al.  The DNA-damage response in human biology and disease , 2009, Nature.

[18]  K. Amara,et al.  Biological significance of promoter hypermethylation of tumor-related genes in patients with gastric carcinoma. , 2009, Clinica chimica acta; international journal of clinical chemistry.

[19]  R. Kaneva,et al.  Promoter hypermethylation of CDKN2A, MGMT, MLH1, and DAPK genes in laryngeal squamous cell carcinoma and their associations with clinical profiles of the patients , 2014, Head & neck.

[20]  Mads Thomassen,et al.  Association of type and location of BRCA1 and BRCA2 mutations with risk of breast and ovarian cancer. , 2015, JAMA.

[21]  P. Assumpção,et al.  Promoter hypermethylation of CDH1, FHIT, MTAP and PLAGL1 in gastric adenocarcinoma in individuals from Northern Brazil. , 2007, World journal of gastroenterology.

[22]  Weidong Wang.  Emergence of a DNA-damage response network consisting of Fanconi anaemia and BRCA proteins , 2007, Nature Reviews Genetics.

[23]  N. Riaz.  DNA methylation in lung cancer. , 2008, The New England journal of medicine.

[24]  J. Herman,et al.  Epigenome-based personalized medicine in human cancer. , 2016, Epigenomics.

[25]  J. Minna,et al.  Expression of the candidate tumor suppressor gene hSRBC is frequently lost in primary lung cancers with and without DNA methylation , 2005, Oncogene.

[26]  Y. Cheng,et al.  Xeroderma pigmentosum group C gene expression is predominantly regulated by promoter hypermethylation and contributes to p53 mutation in lung cancers , 2007, Oncogene.

[27]  G. Strathdee,et al.  A role for methylation of the hMLH1 promoter in loss of hMLH1 expression and drug resistance in ovarian cancer , 1999, Oncogene.

[28]  S. Chi,et al.  Frequent inactivation of hSRBC in ovarian cancers by promoter CpG island hypermethylation , 2010, Acta obstetricia et gynecologica Scandinavica.

[29]  M. Fackler,et al.  Methylation is less abundant in BRCA1-associated compared with sporadic breast cancer. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[30]  Manel Esteller,et al.  Epigenetic modifications in breast cancer and their role in personalized medicine. , 2013, The American journal of pathology.

[31]  B. Price,et al.  Methylation of the ATM promoter in glioma cells alters ionizing radiation sensitivity. , 2006, Biochemical and biophysical research communications.

[32]  J. Herman,et al.  Emerging evidence for CHFR as a cancer biomarker: from tumor biology to precision medicine , 2013, Cancer and Metastasis Reviews.

[33]  P. Hegde,et al.  MPDL3280A (anti-PD-L1) treatment leads to clinical activity in metastatic bladder cancer , 2014, Nature.

[34]  T. Iwama,et al.  Molecular nature of colon tumors in hereditary nonpolyposis colon cancer, familial polyposis, and sporadic colon cancer. , 1996, Gastroenterology.

[35]  M. Esteller,et al.  Epigenetic profiling joins personalized cancer medicine , 2013, Expert review of molecular diagnostics.

[36]  N. H. Khattar,et al.  Genetic and epigenetic modification of mismatch repair genes hMSH2 and hMLH1 in sporadic breast cancer with microsatellite instability , 2002, Oncogene.

[37]  Michael Jones,et al.  Intragenic ATM methylation in peripheral blood DNA as a biomarker of breast cancer risk. , 2012, Cancer research.

[38]  J. Herman,et al.  Generating mutations but providing chemosensitivity: the role of O6-methylguanine DNA methyltransferase in human cancer , 2004, Oncogene.

[39]  Qin Chen,et al.  GPX3 hypermethylation serves as an independent prognostic biomarker in non-M3 acute myeloid leukemia. , 2015, American journal of cancer research.

[40]  M. Dolan,et al.  Inactivation of O6-alkylguanine DNA alkyltransferase as a means to enhance chemotherapy. , 2006, Cancer treatment reviews.

[41]  Q. Wei,et al.  Nucleotide excision repair as a marker for susceptibility to tobacco‐related cancers: A review of molecular epidemiological studies , 2005, Molecular carcinogenesis.

[42]  M. Kloor,et al.  Somatic hypermethylation of MSH2 is a frequent event in Lynch Syndrome colorectal cancers. , 2010, Cancer research.

[43]  Bjørn Naume,et al.  Integrated analysis of high‐resolution DNA methylation profiles, gene expression, germline genotypes and clinical end points in breast cancer patients , 2014, International journal of cancer.

[44]  J. Hoeijmakers,et al.  Nucleotide excision repair and human syndromes. , 2000, Carcinogenesis.

[45]  M. Esteller,et al.  DNA methylation profiling in the clinic: applications and challenges , 2012, Nature Reviews Genetics.

[46]  S. Chi,et al.  Frequent epigenetic inactivation of hSRBC in gastric cancer and its implication in attenuated p53 response to stresses , 2007, International journal of cancer.

[47]  S. Ahrendt,et al.  The XRCC1 codon 399 Gln allele is associated with adenine to guanine p53 mutations in non-small cell lung cancer. , 2003, Mutation research.

[48]  J. Jónasson,et al.  Epigenetic silencing and deletion of the BRCA1 gene in sporadic breast cancer , 2006, Breast Cancer Research.

[49]  David C. Smith,et al.  Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. , 2012, The New England journal of medicine.

[50]  O. Schärer,et al.  DNA Interstrand Crosslinks: Natural and Drug‐Induced DNA Adducts that Induce Unique Cellular Responses , 2005, Chembiochem : a European journal of chemical biology.

[51]  P. Hou,et al.  Hypermethylation of the DNA mismatch repair gene hMLH1 and Its association with lymph node metastasis and T1799A BRAF mutation in patients with papillary thyroid cancer , 2008, Cancer.

[52]  J. Cameron,et al.  Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms. , 2003, Surgery.

[53]  Peter W. Laird,et al.  Molecular Characterization of MSI-H Colorectal Cancer by MLHI Promoter Methylation, Immunohistochemistry, and Mismatch Repair Germline Mutation Screening , 2008, Cancer Epidemiology Biomarkers & Prevention.

[54]  D. Lilley,et al.  Human MutSalpha recognizes damaged DNA base pairs containing O6-methylguanine, O4-methylthymine, or the cisplatin-d(GpG) adduct. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[55]  Hiroyuki Yamamoto,et al.  Microsatellite instability: an update , 2015, Archives of Toxicology.

[56]  Curt I Civin,et al.  Personalized synthetic lethality induced by targeting RAD52 in leukemias identified by gene mutation and expression profile. , 2013, Blood.

[57]  S. Toyooka,et al.  DNA methylation in lung cancer. , 2008, The New England journal of medicine.

[58]  S. Willems,et al.  p16INK4A and p14ARF Gene Promoter Hypermethylation as Prognostic Biomarker in Oral and Oropharyngeal Squamous Cell Carcinoma: A Review , 2014, Disease markers.

[59]  S. Madhusudan,et al.  DNA repair in cancer: emerging targets for personalized therapy , 2014, Cancer management and research.

[60]  D. Matei,et al.  The Novel, Small-Molecule DNA Methylation Inhibitor SGI-110 as an Ovarian Cancer Chemosensitizer , 2014, Clinical Cancer Research.

[61]  C. Tzao,et al.  Epigenetic Inactivation of the Chromosomal Stability Control Genes BRCA1, BRCA2, and XRCC5 in Non–Small Cell Lung Cancer , 2007, Clinical Cancer Research.

[62]  P. Karran,et al.  DNA damage tolerance, mismatch repair and genome instability , 1994, BioEssays : news and reviews in molecular, cellular and developmental biology.

[63]  A. Sartori,et al.  Targeting DNA double-strand break signalling and repair: recent advances in cancer therapy. , 2013, Swiss medical weekly.

[64]  K. Kinzler,et al.  The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints , 2015, Journal of Immunotherapy for Cancer.

[65]  J. Minna,et al.  Aberrant promoter methylation of multiple genes in non-small cell lung cancers. , 2001, Cancer research.

[66]  L. Aaltonen,et al.  The DNA repair gene MBD4 (MED1) is mutated in human carcinomas with microsatellite instability , 1999, Nature Genetics.

[67]  B. Vogelstein,et al.  PD-1 blockade in tumors with mismatch repair deficiency. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[68]  B. Leggett,et al.  Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. , 2001, The American journal of pathology.

[69]  Hua-yun Chen,et al.  Role of ERCC1 promoter hypermethylation in drug resistance to cisplatin in human gliomas , 2010, International journal of cancer.

[70]  N. M. A. El-Maqsoud,et al.  Head and neck squamous cell carcinoma: mismatch repair immunohistochemistry and promoter hypermethylation of hMLH1 gene. , 2011, American journal of otolaryngology.

[71]  David I. K. Martin,et al.  Germline epimutation of MLH1 in individuals with multiple cancers , 2004, Nature Genetics.

[72]  Z. Herceg,et al.  Epigenetic drivers and genetic passengers on the road to cancer. , 2008, Mutation research.

[73]  S. Ganesan,et al.  Interaction of the Fanconi anemia proteins and BRCA1 in a common pathway. , 2001, Molecular cell.

[74]  M. Esteller,et al.  MGMT hypermethylation: a prognostic foe, a predictive friend. , 2007, DNA repair.

[75]  A. Ashworth,et al.  Exploiting the DNA repair defect in BRCA mutant cells in the design of new therapeutic strategies for cancer. , 2005, Cold Spring Harbor symposia on quantitative biology.

[76]  J. Peto,et al.  Gene-body hypermethylation of ATM in peripheral blood DNA of bilateral breast cancer patients , 2009, Human molecular genetics.

[77]  Il-Jin Kim,et al.  [Hereditary colorectal cancer]. , 2005, The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi.

[78]  Martin L. Miller,et al.  Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer , 2015, Science.

[79]  S. Mukherjee,et al.  Association of FANCC and PTCH1 with the Development of Early Dysplastic Lesions of the Head and Neck , 2012, Annals of Surgical Oncology.

[80]  F. Hanaoka,et al.  Molecular biology of Fanconi anaemia—an old problem, a new insight , 2002, BioEssays : news and reviews in molecular, cellular and developmental biology.

[81]  Chao Han,et al.  Silencing GPX3 Expression Promotes Tumor Metastasis in Human Thyroid Cancer. , 2015, Current protein & peptide science.

[82]  Q. Waisfisz,et al.  Hypermethylation of the FANCC and FANCL Promoter Regions in Sporadic Acute Leukaemia , 2008, Cellular oncology : the official journal of the International Society for Cellular Oncology.

[83]  Yan Peng,et al.  XRCC1 downregulated through promoter hypermethylation is involved in human gastric carcinogenesis , 2010, Journal of digestive diseases.

[84]  K. Nephew,et al.  GPx3 promoter hypermethylation is a frequent event in human cancer and is associated with tumorigenesis and chemotherapy response. , 2011, Cancer letters.

[85]  Guo-Min Li,et al.  Mechanisms and functions of DNA mismatch repair , 2008, Cell Research.

[86]  M. Millenson,et al.  PD-1 blockade with nivolumab in relapsed or refractory Hodgkin's lymphoma. , 2015, The New England journal of medicine.

[87]  K. Brown,et al.  Aberrant methylation of the ATM promoter correlates with increased radiosensitivity in a human colorectal tumor cell line , 2002, Oncogene.

[88]  A. D’Andrea,et al.  Susceptibility pathways in Fanconi's anemia and breast cancer. , 2010, The New England journal of medicine.

[89]  Xiaotian Zhang,et al.  Chk2 down-regulation by promoter hypermethylation in human bulk gliomas. , 2010, Life sciences.

[90]  W. Farrar,et al.  Epigenetic Silencing of the Human Nucleotide Excision Repair Gene, hHR23B, in Interleukin-6-responsive Multiple Myeloma KAS-6/1 Cells* , 2005, Journal of Biological Chemistry.

[91]  B. Dutrillaux,et al.  Mutations in OGG1, a gene involved in the repair of oxidative DNA damage, are found in human lung and kidney tumours , 1998, Oncogene.

[92]  Sudhir Srivastava,et al.  Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. , 2004, Journal of the National Cancer Institute.

[93]  A. Ashworth,et al.  The potential of exploiting DNA-repair defects for optimizing lung cancer treatment , 2012, Nature Reviews Clinical Oncology.

[94]  J. Hoeijmakers.  Genome maintenance mechanisms for preventing cancer , 2001, Nature.

[95]  J. Herman,et al.  Promoter Hypermethylation of Resected Bronchial Margins , 2004, Clinical Cancer Research.

[96]  Antoni Ribas,et al.  Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. , 2013, The New England journal of medicine.

[97]  S. Ghosh,et al.  Association of HPV with genetic and epigenetic alterations in colorectal adenocarcinoma from Indian population , 2015, Tumor Biology.

[98]  M. Gore,et al.  A randomised, phase II trial of the DNA-hypomethylating agent 5-aza-2′-deoxycytidine (decitabine) in combination with carboplatin vs carboplatin alone in patients with recurrent, partially platinum-sensitive ovarian cancer , 2014, British Journal of Cancer.

[99]  V. Esposito,et al.  IDH1 mutation and MGMT methylation status predict survival in patients with anaplastic astrocytoma treated with temozolomide-based chemoradiotherapy , 2014, Journal of Neuro-Oncology.

[100]  Hiroshi Kobayashi,et al.  Hereditary breast and ovarian cancer susceptibility genes (review). , 2013, Oncology reports.

[101]  S. Goodman,et al.  Hypermethylation of the DNA repair gene O(6)-methylguanine DNA methyltransferase and survival of patients with diffuse large B-cell lymphoma. , 2002, Journal of the National Cancer Institute.

[102]  D. Carraro,et al.  Mismatch repair genes in Lynch syndrome: a review , 2009, Sao Paulo medical journal = Revista paulista de medicina.

[103]  P. Johnston,et al.  Molecular mechanisms of drug resistance , 2005, The Journal of pathology.

[104]  Wen Li,et al.  Combined effects methylation of FHIT, RASSF1A and RARβ genes on non-small cell lung cancer in the Chinese population. , 2014, Asian Pacific journal of cancer prevention : APJCP.

[105]  M. Bertagnolli,et al.  Molecular origins of cancer: Molecular basis of colorectal cancer. , 2009, The New England journal of medicine.

[106]  Yuepu Pu,et al.  Promoter methylation status of MGMT, hMSH2, and hMLH1 and its relationship to corresponding protein expression and TP53 mutations in human esophageal squamous cell carcinoma , 2014, Medical Oncology.

[107]  Jae Hyuk Lee,et al.  Aberrant methylation of DNA mismatch repair genes in elderly patients with sporadic gastric carcinoma: A comparison with younger patients , 2010, Journal of surgical oncology.

[108]  K. Yoshihara,et al.  Promoter methylation of DAPK1, FHIT, MGMT, and CDKN2A genes in cervical carcinoma , 2014, International Journal of Clinical Oncology.

[109]  A. Vortmeyer,et al.  Mutation of the uracil DNA glycosylase gene detected in glioblastoma. , 1998, Mutation research.

[110]  F. D. De Braud,et al.  Role of MGMT as biomarker in colorectal cancer. , 2014, World journal of clinical cases.

[111]  J. Sludden,et al.  Reversal of drug resistance in human tumor xenografts by 2'-deoxy-5-azacytidine-induced demethylation of the hMLH1 gene promoter. , 2000, Cancer research.

[112]  T. Hamilton,et al.  Platinum Resistance: The Role of DNA Repair Pathways , 2008, Clinical Cancer Research.

[113]  Baorui Liu,et al.  Correlation between the methylation of SULF2 and WRN promoter and the irinotecan chemosensitivity in gastric cancer , 2013, BMC Gastroenterology.

[114]  Giovanni Parmigiani,et al.  Meta-analysis of BRCA1 and BRCA2 penetrance. , 2007, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[115]  A. Ashworth,et al.  Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2 , 2009, EMBO Molecular Medicine.

[116]  B. Saikia,et al.  p16 hypermethylation: A biomarker for increased esophageal cancer susceptibility in high incidence region of North East India , 2015, Tumor Biology.

[117]  Howard Colman,et al.  MGMT promoter methylation is predictive of response to radiotherapy and prognostic in the absence of adjuvant alkylating chemotherapy for glioblastoma. , 2010, Neuro-oncology.

[118]  M. Irigoyen-Camacho,et al.  hMLH1 promoter methylation is an early event in oral cancer. , 2011, Oral oncology.

[119]  E. Platz,et al.  GSTP1 promoter methylation is associated with recurrence in early stage prostate cancer. , 2014, The Journal of urology.

[120]  M. Fraga,et al.  Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[121]  M. King,et al.  Breast and Ovarian Cancer Risks Due to Inherited Mutations in BRCA1 and BRCA2 , 2003, Science.

[122]  L. Hesson,et al.  The Role of RASSF1A Methylation in Cancer , 2007, Disease markers.

[123]  Aung Ko Win,et al.  Cancer Risks for the Relatives of Colorectal Cancer Cases with a Methylated MLH1 Promoter Region: Data from the Colorectal Cancer Family Registry , 2011, Cancer Prevention Research.

[124]  E. Parlanti,et al.  8-Oxoguanine DNA damage: at the crossroad of alternative repair pathways. , 2003, Mutation research.

[125]  Samuel H. Wilson,et al.  The Werner syndrome protein operates in base excision repair and cooperates with DNA polymerase β , 2006, Nucleic acids research.

[126]  G. Hannon,et al.  A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4 , 1993, Nature.

[127]  M. Esteller,et al.  Epigenetic biomarkers for human cancer: the time is now. , 2008, Critical reviews in oncology/hematology.

[128]  J. Herman,et al.  Methylation of CHFR sensitizes esophageal squamous cell cancer to docetaxel and paclitaxel , 2015, Genes & cancer.

[129]  A. Ashworth,et al.  Hallmarks of 'BRCAness' in sporadic cancers , 2004, Nature Reviews Cancer.

[130]  H. Lieberman,et al.  DNA Damage Response Genes and the Development of Cancer Metastasis , 2014, Radiation research.

[131]  W. Tan,et al.  Inactivation of DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation and its relation to p53 mutations in esophageal squamous cell carcinoma. , 2003, Carcinogenesis.

[132]  Vessela Kristensen,et al.  Methylation profiling with a panel of cancer related genes: Association with estrogen receptor, TP53 mutation status and expression subtypes in sporadic breast cancer , 2011, Molecular oncology.

[133]  A. Niemierko,et al.  Impact of genomic methylation on radiation sensitivity of colorectal carcinoma. , 2010, International journal of radiation oncology, biology, physics.

[134]  Chih-Yi Chen,et al.  Inactivation of hMLH1 and hMSH2 by promoter methylation in primary non-small cell lung tumors and matched sputum samples. , 2003, The Journal of clinical investigation.

[135]  K. Miyazaki,et al.  Aberrant methylation of p16 predicts candidates for 5-fluorouracil-based adjuvant therapy in gastric cancer patients , 2007, Journal of Gastroenterology.

[136]  M. Sabatino,et al.  Down-regulation of the Nucleotide Excision Repair gene XPG as a new mechanism of drug resistance in human and murine cancer cells , 2010, Molecular Cancer.

[137]  M. Wyatt,et al.  Participation of DNA repair in the response to 5-fluorouracil , 2009, Cellular and Molecular Life Sciences.

[138]  Guo-Min Li,et al.  The role of mismatch repair in DNA damage-induced apoptosis. , 1999, Oncology research.

[139]  L. Kasturi,et al.  Biallelic inactivation of hMLH1 by epigenetic gene silencing, a novel mechanism causing human MSI cancers. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[140]  G. Mufti,et al.  Applying synthetic lethality for the selective targeting of cancer. , 2014, The New England journal of medicine.

[141]  E. Hurt,et al.  DNA Hypermethylation and Partial Gene Silencing of Human Thymine-DNA Glycosylase in Multiple Myeloma Cell Lines , 2006, Epigenetics.

[142]  M. Toyota,et al.  Epigenetic drivers of genetic alterations. , 2010, Advances in genetics.

[143]  O. Olopade,et al.  FANCF methylation contributes to chemoselectivity in ovarian cancer. , 2003, Cancer Cell.

[144]  L. Zerbini,et al.  Aberrant methylation of the MSH3 promoter and distal enhancer in esophageal cancer patients exposed to first-hand tobacco smoke , 2014, Journal of Cancer Research and Clinical Oncology.

[145]  Zhimin Chen,et al.  XPC epigenetic silence coupled with p53 alteration has a significant impact on bladder cancer outcome. , 2010, The Journal of urology.

[146]  J. Li,et al.  Methylation of promoter and expression silencing of GPX3 gene in hepatocellular carcinoma tissue. , 2015, Clinics and research in hepatology and gastroenterology.

[147]  J. Herman,et al.  Epigenetic changes associated with neoplasms of the exocrine and endocrine pancreas. , 2014, Discovery medicine.

[148]  M. Esteller,et al.  BRCA1 epigenetic inactivation predicts sensitivity to platinum-based chemotherapy in breast and ovarian cancer , 2012, Epigenetics.

[149]  Nicola J. Curtin,et al.  DNA repair dysregulation from cancer driver to therapeutic target , 2012, Nature Reviews Cancer.

[150]  J. Herman,et al.  Accumulation of Promoter Methylation Suggests Epigenetic Progression in Squamous Cell Carcinoma of the Esophagus , 2006, Clinical Cancer Research.

[151]  R. Stupp,et al.  Epigenetic Deregulation of DNA Repair and Its Potential for Therapy , 2009, Clinical Cancer Research.

[152]  Jun Kato,et al.  Decreased expression of hMLH1 correlates with reduced 5-fluorouracil-mediated apoptosis in colon cancer cells. , 2007, Oncology Report.

[153]  Dong Sun Kim,et al.  Epigenetic inactivation of checkpoint kinase 2 gene in non-small cell lung cancer and its relationship with clinicopathological features. , 2009, Lung cancer.

[154]  T. Halazonetis,et al.  Chfr defines a mitotic stress checkpoint that delays entry into metaphase , 2000, Nature.

[155]  R. Plummer.  Perspective on the Pipeline of Drugs Being Developed with Modulation of DNA Damage as a Target , 2010, Clinical Cancer Research.

[156]  Jin Wook Kim,et al.  Aberrant methylation of Fragile Histidine Triad gene is associated with poor prognosis in early stage esophageal squamous cell carcinoma. , 2006, European journal of cancer.

[157]  J. Herman,et al.  Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. , 2000, Cancer research.

[158]  Chunhe Li,et al.  Quantitative detection of methylation of FHIT and BRCA1 promoters in the serum of ductal breast cancer patients. , 2015, Bio-medical materials and engineering.

[159]  E. Auerkari.  Methylation of tumor suppressor genes p16(INK4a), p27(Kip1) and E-cadherin in carcinogenesis. , 2006, Oral oncology.

[160]  M. Esteller,et al.  Epigenetic Inactivation of the BRCA1 Interactor SRBC and Resistance to Oxaliplatin in Colorectal Cancer , 2013, Journal of the National Cancer Institute.

[161]  D. Sargent,et al.  Molecular Pathways: Microsatellite Instability in Colorectal Cancer: Prognostic, Predictive, and Therapeutic Implications , 2012, Clinical Cancer Research.

[162]  J. Sweasy,et al.  Is Base Excision Repair a Tumor Suppressor Mechanism? , 2006, Cell cycle.

[163]  M. Loda,et al.  Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. , 1997, Cancer research.

[164]  J. Herman,et al.  Predictive value of CHFR and MLH1 methylation in human gastric cancer , 2015, Gastric Cancer.

[165]  A. Godwin,et al.  Epigenetic downregulation of the DNA repair gene MED1/MBD4 in colorectal and ovarian cancer , 2009, Cancer biology & therapy.

[166]  J.,et al.  The New England Journal of Medicine , 2012 .