Modulation of Radiation-Induced Genetic Damage by HCMV in Peripheral Blood Lymphocytes from a Brain Tumor Case-Control Study

Human cytomegalovirus (HCMV) infection occurs early in life and viral persistence remains through life. An association between HCMV infection and malignant gliomas has been reported, suggesting that HCMV may play a role in glioma pathogenesis and could facilitate an accrual of genotoxic damage in the presence of γ-radiation; an established risk factor for gliomas. We tested the hypothesis that HCMV infection modifies the sensitivity of cells to γ-radiation-induced genetic damage. We used peripheral blood lymphocytes (PBLs) from 110 glioma patients and 100 controls to measure the level of chromosome damage and cell death. We evaluated baseline, HCMV-, γ-radiation and HCMV + γ-radiation induced genetic instability with the comprehensive Cytokinesis-Blocked Micronucleus Cytome (CBMN-CYT). HCMV, similar to radiation, induced a significant increase in aberration frequency among cases and controls. PBLs infected with HCMV prior to challenge with γ-radiation led to a significant increase in aberrations as compared to baseline, γ-radiation and HCMV alone. With regards to apoptosis, glioma cases showed a lower percentage of induction following in vitro exposure to γ-radiation and HCMV infection as compared to controls. This strongly suggests that, HCMV infection enhances the sensitivity of PBLs to γ-radiation-induced genetic damage possibly through an increase in chromosome damage and decrease in apoptosis.

[1]  J. Mi,et al.  PP2A regulates ionizing radiation–induced apoptosis through Ser46 phosphorylation of p53 , 2009, Molecular Cancer Therapeutics.

[2]  K. Aldape,et al.  Association and Interactions between DNA Repair Gene Polymorphisms and Adult Glioma , 2009, Cancer Epidemiology Biomarkers & Prevention.

[3]  H. Doerr,et al.  The story of human cytomegalovirus and cancer: increasing evidence and open questions. , 2009, Neoplasia.

[4]  T. Shenk,et al.  Inhibition of cyclooxygenase activity blocks cell-to-cell spread of human cytomegalovirus , 2008, Proceedings of the National Academy of Sciences.

[5]  Tarik Tihan,et al.  Brain tumor epidemiology: Consensus from the Brain Tumor Epidemiology Consortium , 2008, Cancer.

[6]  T. Takemura,et al.  Type AB thymoma accompanied by pure red cell aplasia and Good syndrome with CMV infection of tumor cells , 2008, Pathology international.

[7]  M. Fenech,et al.  Cytokinesis-Blocked Micronucleus Cytome Assay Biomarkers Identify Lung Cancer Cases Amongst Smokers , 2008, Cancer Epidemiology Biomarkers & Prevention.

[8]  K. Aldape,et al.  Detection of human cytomegalovirus in different histological types of gliomas , 2008, Acta Neuropathologica.

[9]  K. Ohuchida,et al.  Radiation Enhances Adenoviral Gene Therapy in Pancreatic Cancer via Activation of Cytomegalovirus Promoter and Increased Adenovirus Uptake , 2008, Clinical Cancer Research.

[10]  S. Bonassi,et al.  Validation of micronuclei frequency in peripheral blood lymphocytes as early cancer risk biomarker in a nested case-control study. , 2008, Mutation research.

[11]  In Sup Kil,et al.  Regulation of Ionizing Radiation-induced Apoptosis by Mitochondrial NADP+-dependent Isocitrate Dehydrogenase* , 2007, Journal of Biological Chemistry.

[12]  M. Fenech.  Cytokinesis-block micronucleus cytome assay , 2007, Nature Protocols.

[13]  M. Spitz,et al.  Mutagen sensitivity: a genetic predisposition factor for cancer. , 2007, Cancer research.

[14]  F. Meyskens,et al.  UC Irvine UC Irvine Previously Published Works Title Reactive oxygen species : a breath of life or death ? , 2007 .

[15]  D. Leibfritz,et al.  Free radicals and antioxidants in normal physiological functions and human disease. , 2007, The international journal of biochemistry & cell biology.

[16]  Margaret Wrensch,et al.  Epidemiology and molecular pathology of glioma , 2006, Nature Clinical Practice Neurology.

[17]  M. Spitz,et al.  Cytokinesis-blocked micronucleus assay as a novel biomarker for lung cancer risk. , 2006, Cancer research.

[18]  T. Shenk,et al.  Human cytomegalovirus inhibits a DNA damage response by mislocalizing checkpoint proteins. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[19]  M. Berger,et al.  The molecular epidemiology of gliomas in adults. , 2005, Neurosurgical focus.

[20]  H. Mozdarani,et al.  Cytogenetic radiosensitivity of g0-lymphocytes of breast and esophageal cancer patients as determined by micronucleus assay. , 2005, Journal of radiation research.

[21]  M. Relling,et al.  Lymphoid gene expression as a predictor of risk of secondary brain tumors , 2005, Genes, chromosomes & cancer.

[22]  J. Marcello,et al.  Induction of latent human cytomegalovirus by conventional gamma irradiation and prevention by treatment with INACTINE PEN110 , 2004, Vox sanguinis.

[23]  M. Fons,et al.  Differential mutagen sensitivity of peripheral blood lymphocytes from smokers and nonsmokers: Effect of human cytomegalovirus infection , 2004, Environmental and molecular mutagenesis.

[24]  M. Fenech,et al.  HUMN project: detailed description of the scoring criteria for the cytokinesis-block micronucleus assay using isolated human lymphocyte cultures. , 2003, Mutation research.

[25]  J. Vávrová,et al.  Modulation of ionizing radiation-induced apoptosis and cell cycle arrest by all-trans retinoic acid in promyelocytic leukemia cells (HL-60). , 2003, Physiological research.

[26]  C. Cobbs,et al.  Human cytomegalovirus infection and expression in human malignant glioma. , 2002, Cancer research.

[27]  J. Bruner,et al.  γ-Radiation Sensitivity and Risk of Glioma , 2001 .

[28]  T. Chittenden,et al.  A cytomegalovirus-encoded inhibitor of apoptosis that suppresses caspase-8 activation , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[29]  F. McCormick,et al.  Transcriptional activation of TRADD mediates p53-independent radiation-induced apoptosis of glioma cells , 2001, Oncogene.

[30]  J. Gurney,et al.  Brain and other central nervous system tumors: rates, trends, and epidemiology , 2001, Current opinion in oncology.

[31]  J. Bruner,et al.  Gamma-radiation sensitivity and risk of glioma. , 2001, Journal of the National Cancer Institute.

[32]  M. Fenech,et al.  HUman MicroNucleus project: international database comparison for results with the cytokinesis‐block micronucleus assay in human lymphocytes: I. Effect of laboratory protocol, scoring criteria, and host factors on the frequency of micronuclei , 2001, Environmental and molecular mutagenesis.

[33]  F. Davis,et al.  Epidemiology of brain tumors. , 2000, Current opinion in neurology.

[34]  T. Shenk,et al.  Replication of Wild-Type and Mutant Human Cytomegalovirus in Life-Extended Human Diploid Fibroblasts , 2000, Journal of Virology.

[35]  M. Relling,et al.  High incidence of secondary brain tumours after radiotherapy and antimetabolites , 1999, The Lancet.

[36]  M. Spitz,et al.  Mutagen sensitivity to benzo(a)pyrene diol epoxide and the risk of squamous cell carcinoma of the head and neck. , 1998, Clinical cancer research : an official journal of the American Association for Cancer Research.

[37]  M. Fons,et al.  Increased frequency of specific locus mutation following human cytomegalovirus infection. , 1997, Virology.

[38]  J. Bruner,et al.  Mutagen sensitivity and risk of gliomas: a case-control analysis. , 1996, Cancer research.

[39]  D. Christiani,et al.  Increased micronucleus frequency in lymphocytes from smokers with lung cancer. , 1996, Mutation research.

[40]  T. Shenk,et al.  Human cytomegalovirus IE1 and IE2 proteins block apoptosis. , 1995, Journal of virology.

[41]  M. Fons,et al.  Cytomegalovirus‐enhanced induction of chromosome aberrations in human peripheral blood lymphocytes treated with potent genotoxic agents , 2006, Environmental and molecular mutagenesis.

[42]  M. Fons,et al.  Modulation of the frequency of human cytomegalovirus-induced chromosome aberrations by camptothecin. , 1992, Virology.

[43]  L. Hodges,et al.  Prevalence of Glioblastoma Multiforme in Subjects with Prior Therapeutic Radiation , 1992, The Journal of neuroscience nursing : journal of the American Association of Neuroscience Nurses.

[44]  A. Goddard,et al.  Chromosome aberrations and cancer. , 1991, Science.

[45]  M. Fons,et al.  Activation of cellular oncogenes by clinical isolates and laboratory strains of human cytomegalovirus , 1991, Journal of medical virology.

[46]  T. Albrecht,et al.  Activation of proto-oncogenes: an immediate early event in human cytomegalovirus infection. , 1990, Science.

[47]  T. Albrecht,et al.  Human cytomegalovirus. Stimulation of [3H] release from [3H]-arachidonic acid prelabelled cells. , 1990, Archives of virology.

[48]  W. Ho,et al.  Reciprocal enhancement of gene expression and viral replication between human cytomegalovirus and human immunodeficiency virus type 1. , 1990, Disease markers.

[49]  M. Fons,et al.  Cell-Activation Responses to Cytomegalovirus Infection , 1989 .

[50]  M. Fons,et al.  Cell-activation responses to cytomegalovirus infection relationship to the phasing of CMV replication and to the induction of cellular damage. , 1989, Sub-cellular biochemistry.

[51]  T. Albrecht,et al.  Induction of chromosome aberrations and mitotic arrest by cytomegalovirus in human cells. , 1988, Environmental and molecular mutagenesis.

[52]  M. Dion,et al.  Relationship between enhanced reactivation and mutagenesis of u.v.‐irradiated human cytomegalovirus in normal human cells. , 1987, The EMBO journal.

[53]  J. Shanley.  Human Cytomegalovirus Replicates in Gamma‐Irradiated Fibroblasts , 1986, Journal of medical virology.

[54]  E. Huang,et al.  Human cytomegalovirus and herpes simplex type 2 virus in normal and adenocarcinomatous prostate glands. , 1983, Journal of the National Cancer Institute.

[55]  H. Evans,et al.  Human peripheral blood lymphocytes for the analysis of chromosome aberrations in mutagen tests. , 1975, Mutation research.