CONTENTS GENERAL REMARKS Epstein-Barr virus...47

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1 CONTENTS NOTE TO THE READER LIST OF PARTICIPANTS PREAMBLE Background Objective and Scope Selection of Topies for Monographs Data for Monographs The W orking Group W orking Procedures Exposure Data Studies of Cancer in Humans Studies of Cancer in Experimental AnimaIs...17 Other Data Relevant to an Evaluation of Carcinogenieity and Hs Mechanisms...20 Summar of Data Reported Evaluation References GENERAL REMARKS INTRODUCTION Structure of herpesviruses The virion Genornc organization Taxonomy of herpesviruses Alphaherpesvirses Betaherpesviruses Gamaherpesviruses CUITent classification Herpesviruses and human disease THE MONOGRAPHS Epstein-Barr virus Virus-host interactions Structure, taxonomy and viral gene products Strctue

2 iv IARC MONOGRAPRS VOLUME Taxonomy Host range Target cells Genome, episomal and integrated virus forms and gene products EB V -encoded RNAs Nuclear proteins (a) EBNA -LP (b) EBNA (c) EBNA-3A, -3B, -3C...58 (d) EBNA-l Latent membrane proteins (a) LMP-l (b) LMP-2A and -2B Other latent viral genes Genes of the productive viral cycle...62 (a) Immediate early genes...63 (b) Early genes (c) Late genes Methods of detection Assays to detect antibodies to EBV Immunofluorescence Enzyme-linked immunosorbent assay Imunoblotting Complement fixation Functional assays Detection of EBV in tissues Southern blot hybridization and the polymerase chain reaction ln-situ hybridization and immunohistochemistry Biology of EBV infection Target tissues Infection in vitro Infection of non-neoplastic cells in vivo Infection in neoplasms Persistence and latency Immune responses Antibody responses Cell-mediated responses Epidemiology of EBV infection Clinical conditions other than malignancy Infectious mononucleosis Oral hai leukoplaka The X-lied lymphoproliferative syndrome...88

3 CONTENTS v 1.6 Control and prevention Drugs Prospects for vaccines Selection of an EBV vaccine antigen molecule Animal models of EBV infection, disease and vaccination Natural gp350 subunit vaccines Recombinant gp350 subunit vaccines T- and B-cell epitopes on the gp350 molecule ChoIce of adjuvant Live virs-vector recombinants Cell-mediated immune responses to gp Vaccines against EBV latent antigens Conclusions Passive immunotherapy Studies of cancer in humans Burkitt' s lymphoma Clinical features and pathology Clinical features......; Gross pathology Histological characteristics Descriptive epidemiology Historical aspects Incidence Climatic deterrnants Time-space clustering Familial cases Epidemiology of Burkitt' s lymphoma in association with EBV Case series (a) Afrcan patients (b) Non-Afrcan patients Case-control studies (a) African patients (b) Non-African patients Cohort study Cofactors Malara (a) Ecological studies (b) Relationship between BurkItts lymphoma and sickle-cell trait (c) Intervention study Euphorbia tirucall and other medicinal plants Molecular epidemiology

4 VI IARC MONOGRAHS VOLUME Non-Hodgkin's lymphomas other than Burkitt's lymphoma Pathology Epidernology Descriptive epidemiology Case reports and case series (a) B-Cell non-hodgkin's lymphoma (b) Angiocentric T-cell lymphoma (c) Other peripheral T-cell lymphomas Cohort studies Human immunodeficiency virus as a cofactor Primar central nervous system lymphomas Systemic non-hodgkin's lymphomas Congenital immunodeficiency syndromes Hodgkin' s disease Pathology and c1inical features Epidernology Descriptive epidemiology Association with EB V (a) Case reports and case series (b) Case-control studies (c) Cohort studies N asopharngeal carcinoma Clinical features and histopathology Clinical features Histopathology Epidernology Descriptive epidemiology (a) International patterns (b) Migration (c) Sex and age (d) Race and ethnicity (e) Socioeconomic status if Urbanization (g) Time trends (h) Correlation with age-specifie prevalence of EBV infection Case series (a) Antibodies in sera and thoat washings (b) Nuc1eic acid markers in carcinoma cells (c) Viral gene expression in tumour specimens Case-control studies (a) Based on pre-diagnostic serological tests (b) Based on serological tests at time of diagnosis Cohort studies

5 CONTENTS vu Mass serological surveys Cofactors Dietar factors (a) Cantonese-style salted fish (b) Other types of salted fish (c) Other preserved foods (d) Deficits of fresh vegetables and fruit Other environmental factors (a) Fumes, smoke and dust (b) Formaldehyde (c) Tobacco (d) AlcohoL (e) Herbal drugs if Incense and anti-mosquito coils (g) Chinese nasal oïl Host factors Familial aggregation Comparson of characteristics of Burkitt' s lymphoma, Hodgkin' s disease and nasopharngeal carcinoma Other malignancies Lymphoepithelial carcinomas outside the nasopharnx Other carcinomas Stomach Other sites Smooth-musc1e tumours Other tumours Studies of cancer in animais EB V in non-human species Infection of non-human primates with EBV New W orld primates Old W orld primates...~ Transformation of monkey cells by EBV in vitro Rodent models for EBV infection and pathogenesis Severe combined immunodeficiency (SCID) mouse model Nude mouse model EBV-like virses isolated from non-human primates Herpesvirus papio (cercopithecine herpesvirs 12) Celllines, persistence and transformation Prevalence of infection with Herpesvirus papio Molecular biology A Pathogenesis and immune response to Herpesvirus papio

6 Vll IAC MONOGRAPHS VOLUME Gama-l herpesvirs from cynomolgus monkey (Macaca jascicuzaris) Rabbit model of malignant lymphoma induced by EBV -like virs from Macaca arctoïdes Other models of relevance to EB V Murid herpesvirus Marek' s disease Other data relevant to an evaluation of carcinogenicity and its mechanisms Growth transformation Role of EB V Minimal set of transforrng genes Growth transformation in vitro and induction of lymphoproliferation in vivo Viral transcription pattern after infection of human primar B lymphocytes by EBV Viral proteins involved in growth transformation EBNA EBNA-LP EBNA EBNA-3A, -3B and -3C LMP-l LMP-2A and -2B Cellular genes induced during growth transformation by EBV Burkitt' s lymphoma Molecular abnormalities in relation to the tumour-cell precursor Translocation of the c-myc oncogene The Burkitt's lymphoma-cell phenotype resembles that of a germnal-centre cell Mutations in p53 in Burkitt' s lymphoma EBV infection in Burkitts lymphoma EBV is monoclonal in Burkitt's lymphoma Integration of viral DNA in Burkitts lymphoma cells Expression of EBV genes in EBV -associated Burkitts lymphoma Expression only of EBNA -1 is associated with reduced immunogenicity The proliferation programe driven by c-myc-imunoglobulin is incompatible with expression of EBNA-2 and LMP-l in the type-ii latency programe Contrbution of the virai strategy for latent persistence to lymphomagenesis EBNA-1 subtypes Effects of malara on B-cell activation and EBV infection Plant products

7 CONTENTS ix Genetic disposition Burkitt's lymphoma in AIDS patients Other non-hodgkin's lymphomas and lymphoproliferative conditions Immunosuppressed patients Primar immune defects due to genetic abnormalities with EBV-positive lymphoproliferation as one consequence Post-transplant lymphoproliferative disorders AIDS (a) Viral factors (b) Disturbances of immunity as cofactors (c) Oncogenes and genetic abnormalities as possible cofactors (d) Pathogenesis of EBV -associated, AIDS-related non-hodgkin's lymphoma: A scenaro T -Cell lymphomas Hodgkin' s disease N asopharngeal carcinoma EBV infection Molecular and biochemical studies EB V expression Phenotype and cellular gene expression EBV infection and transformation of epithelial cells in vitro Detection of EBV infection in normal, premalignant and malignant nasopharngeal tissues Strain varation Contribution of environmental and genetic factors Dietar cofactors (a) Experients in rodents (b) High-risk populations Genetic factors Other malgnancies, inc1uding lymphoepithelial carcinomas Immune responses and EBV-associated malignancies B-Cell lymphoma and other tumours associated with severe immunosuppression Burkitt' s lymphoma Hodgkin' s disease Nasopharngeal carcinoma Summar of data reported and evaluation Virs-host interactions Human carcinogenicity Burkitt' s lymphoma Non-Hodgkin' s lymphomas

8 x IARC MONOGRAPHS VOLUME Hodgkin' s disease Nasopharngeal carcinoma Other tumours Studies of cancer in animais Other relevant data Burkitt' s lymphoma Non-Hodgkin's lymphomas and lymphoproliferation Hodgkin' s disease N asopharngeal carcinoma Other malignancies, including lymphoepithelial carcinomas Evaluation References Kaposi's sarcoma herpesvirus/human herpesvirus Virus-host interactions Taxonomy, structure and biology Taxonomy Structure Morphology Genomic structure and properties of gene products (a) Terrnal-repeat region (b) Long unique region ~ Strain varation Host range Related non-human viruses Tropism and persistence of infected cells in vivo Persistence and gene expression in infected endothelial cells Persistence in haematopoietic cells Presence in other tissues Methods of detection Nucleic acids Serology Culture in vitro Epidernology of infection......: Prevalence in peripheral blood mononuclear cells Prevalence in semen Seroprevalence and geographical distrbution Routes of transmission Control and prevention Studies of cancer in humans Kaposi' s sarcoma Pathology and clinical disease Epidemiological ard c1inical presentation...396

9 CONTENTS XI Histology Epidernology Incidence and geographical distribution Demographic variations Behavioural factors Second primar malignancies after Kaposi's sarcoma Case series and case-control studies Detection of KSHV IHHV8 DNA in tumour tissue Detection of KSHVIHHV8DNA in peripheral blood mononuclear cells Detection of KSHVIHHV8 DNA in other tissues Serology Temporal associations Lymphoproliferative disorders Primar effusion lymphomas Pathology and clinical presentation Descriptive epidemiology Case reports and case series Castleman' s disease Pathology and clinical presentation Descriptive epidemiology Case reports and case series Multiple myeloma Other lymphoproliferative disorders Other tumours Studies of cancer in animal models Herpesvirus saimiri (saimiriine herpesvirus 2) Description Host range, virus isolation and virus multiplication Host response: antibody detection Human exposure Molecular aspects Oncogenicity in non-human primates, rabbits and transgenic rnce Transformation of mamalian cells in vitro Herpesvirus ateles (ateline herpesvirus 2) Description Host range, cytopathogenicity and viral multiplication Molecular analysis Oncogenicity in non-human primates Bovine herpesvirus 4 (Movar herpesvirus) Classification Description Host range

10 XlI IARC MONOGRAPHS VOLUME Natural transmission Evidence that bovine herpesvirus 4 causes disease Isolates Murid herpesvirs Retroperitoneal fibromatosis herpesviruses Other data relevant to an evaluation of carcinogenesis and its mechanisms Kaposi' s sarcoma Cell biology Origin of spindle cells Vascular lesions induced by Kaposi' s sarcoma cell cultures in nude mice Growth factors involved in proliferation of spindle cells..448 (a) Fibroblast growth factors (b) Platelet-derived growth factor (c) Interleukin-l (d) Interleukin (e) Tumour necrosis factor a if Miscellaneous growth factors Role of HIV -1 Tat in promoting Kaposi' s sarcoma lesions Clonality of Kaposi' s sarcoma lesions Role of KSHV/HHV8 in development of Kaposi's sarcoma Primar effusion lymphomas Multicentrc Castleman' s disease Viral genes with cellular growth promoting or oncogenic potential Open reading rame Kl Growth factor homologues bcl-2 homologue Viral interferon regulatory factor Viral proteins that inhbit fas-associated death domain protein interleukin-l ß converting enzyme (FLICE) Viral cycli Latency-associated nuclear antigen G Protein-coupled receptor homologue Summar of potential roles of KSHV 1H8 in tumorigenesis Kaposi' s sarcoma Primar effusion lymphoma Multicentrc Castleman' s disease Antiviral agents Sumar of data reported and evaluation...; Virus-host interactions Human carcinogenicity , Anal models ,4 Molecular mechansms of carcinogenesis...462

11 CONTENTS Xl1 5.5 Evaluation References ABBREVIA TIONS SUPPLEMENTARY CORRGENDA TO VOLUMS CUMULATIVE INEX TO THE MONOGRAPHS SERIS...497

12 NOTE TO THE READER The term 'carcinogenic risk' in the IARC Monographs series is taken to mean the probability that exposure to an agent will lead to cancer in humans. Inclusion of an agent in the Monographs does not imply that it is a carcinogen, only that the published data have been exarnned. Equally, the fact that an agent hàs not yet been evaluated in a monograph does not mean that it is not carcinogenic. The evaluations of carcinogenic risk are made by international working groups of independent scientists and are qualitative in nature. No rccommendation is given for regulation or legislation. Anyone who is aware of published data that may alter the evaluation of the carcinogenic risk of an agent to humans is encouraged to make this information available to the Unit of Carcinogen Identification and Evaluation, International Agency for Research on Cancer, 150 cours Albert Thomas, Lyon Cedex 08, France, in order that the agent may be considered for re-evaluation by a future W orking Group. Although every effort is made to prepare the monographs as accurately as possible, mistakes may occur. Readers are requested to communicate any errors to the Unit of Carcinogen Identification and Evaluation, so that corrections can be reported in future volumes. -1-