A Glimpse on Viral Oncogenesis and Epidemiology of

A Glimpse on Viral Oncogenesis and Epidemiology of HIV/AIDS related Non-Hodgkin Lymphoma Weiming ZHU Nov 6, 2009

Non-Hodgkin Lymphoma n n n ICD-10 C 82 -C 85 C 82 Follicular [nodular] non-Hodgkin's lymphoma C 83 Diffuse non-Hodgkin's lymphoma C 83. 3 Large cell (diffuse) C 83. 7 Burkitt's tumour n n C 84 C 85 Peripheral and cutaneous T-cell lymphomas Other and unspecified types of non-Hodgkin's lymphoma

Parkin DM, et al, Cancer incidence in five continents, 2002

Parkin DM, et al, Cancer incidence in five continents, 2002

Incidence of NHL, SEER Incidence Rates by Race 2002 -2006 Race/Ethnicity Male Female All Races 23. 5 per 100, 000 men 16. 4 per 100, 000 women White 24. 4 per 100, 000 men 17. 2 per 100, 000 women Black 18. 3 per 100, 000 men 12. 2 per 100, 000 women Asian/Pacific Islander 15. 5 per 100, 000 men 10. 9 per 100, 000 women American Indian/Alaska Native a 11. 8 per 100, 000 men 10. 0 per 100, 000 women Hispanic b 19. 1 per 100, 000 men 14. 6 per 100, 000 women

Mortality of NHL, SEER Death Rates by Race 2002 -2006 Race/Ethnicity Male Female All Races 9. 0 per 100, 000 men 5. 7 per 100, 000 women White 9. 3 per 100, 000 men 5. 9 per 100, 000 women Black 6. 3 per 100, 000 men 4. 1 per 100, 000 women Asian/Pacific Islander 5. 4 per 100, 000 men 3. 7 per 100, 000 women American Indian/Alaska Native a 5. 2 per 100, 000 men 4. 4 per 100, 000 women Hispanic b 6. 4 per 100, 000 men 4. 6 per 100, 000 women

Estimated NHL in US, 2009 n New cases: 65, 980 n Deaths: 19, 500 http: //www. cancer. gov/cancertopics/types/non-hodgkin

Risk Factors of NHL n Occupational and environmental factors Pesticide : Occupational and environmental n Lifestyle and personal factors Tobacco and alcohol use, Dietary factors, BMI Hair dyes, Hormonal and reproductive factors, Physical activity n Family history and Genetic factors Family history, Genetic variation (SNP) DD. Alexander et al. Int. J. Cancer: 120, 1– 39 (2007)

Risk Factors of NHL n Infection & Immunity Example: Burkitt Lymphoma First Epidemiological Report: Epidemiological evidence for causal relationship between Epstein-Barr virus and Burkitt's lymphoma from Ugandan prospective study Nature 274, 756 - 761 (24 August 1978) Glemser B. Mr Burkitt and Africa. 1970.

HIV/AIDS related NHL “Outbreak” in 1982 “The second unusual malignancy among this group of young males” Diffuse, Undifferentiated Non-Hodgkin’s Lymphoma among Homosexual Males -- United States MMWR June 04, 1982 / 31(21); 277 -9

HIV/AIDS related NHL Lancet 1991; 337: 805– 09

Lancet 1998; 351: 1833– 39

HIV/AIDS associated NHL n n n n n Primary Effusion Lymphoma / PEL ‘Solid’ lymphomas with serous effusions ‘Solid’ lymphomas without serous effusions Large B-cell lymphoma arising in KSHV-associated MCD Immunodeficiency-associated Burkitt Lymphomaplasmacytoid lymphoma Primary central nervous system lymphoma DLBCL, immunoblastic-plasmacytoid lymphoma KSHV/HHV 8 -positive PEL and its solid variant Plasmablastic lymphoma of the oral cavity type PEL

A Carbone et al, Blood. 2009; 113: 1213 -1224

Burkitt Lymphoma. Ed Uthman, MD. , Wikipedia

H. Löffler, J. Rastetter, T. Haferlach. Atlas of Clinical Hematology 6 ed.

Plasmablastic Lymphoma A Carbone et al, Blood. 2009; 113: 1213 -1224

Viral Oncogenesis of NHL n n Epstein-Barr Virus Kaposi Sarcoma-associated Herpesvirus A Arvin et al, Human Herpesvirus. 2007. pp 342. Fig. 22. 1.

A Carbone et al, Blood. 2009; 113: 1213 -1224

Epstein-Barr Virus

Epstein-Barr Virus Subfamily Gammaherpesvirinae Genus Lymphocryptovirus Formal Name: Human herpesvirus 4 / HHV-4 n Common Name: Epstein-Barr virus / EBV n

Seroepidemiology n n n Kenya, 94% of children are EBV seropositive by 3 years of age (Moormann et al. 2005). similar in Nigeria (Martro et al. 2004) , Ethiopia (Tsega et al. 1987). Children in Hong Kong were reported to be 61% EBV seropositive by 2 years (Chan et al. 2001) Germany and USA between 45% and 47% (Martro et al. 2004)

Transmission of EBV n n General: Saliva Oropharyngeal secretions Rare Blood Transfusion

Target Cells of EBV n n Major B-lymphocytes Epithelial cells Other T-cells NK-cells Smooth Muscle Cells Follicular Dendritic Cells (possible)

Molecular Epidemiology n EBV type 1 B 95 -8 cell line, a patient of infectious mononucleosis (IM) , USA n EBV type 2 AG 876 strain, a patient with endemic Burkitt’s lymphoma, Ghana Different in capacity of Transformation Type 1: Transforms cells in culture Type 2: Poorly transforming, reactivates from latency

Molecular Epidemiology n n n Type 1 is the dominant strain in Western countries A higher prevalence of Type 2 in South America Relatively equal in some African countries (Zimber et al. 1986; Yao et al. 1991 b; Gratama et al. 1994; Falk et al. 1997: Young, 1987 #453). Co-infection of Type 1 and Type 2 Less than 10% of adults tested in US and European High in HIV-infected homosexual males and transplant recipients (Katz et al. 1988; Sixbey et al. 1989; Gratama et al. 1994; Yao et al. 1996).

Molecular Epidemiology n n Type 1 predominates in most EBVassociated malignancies : Nasopharyngeal carcinoma, Hodgkin’s lymphoma, and Post-transplant lymphoma Type 2 detected in tumors, particularly those arising in Men who have Sex with Men (MSM) and are HIV infected A Tselis, HB Jenson. Epstein-Barr virus 2006.

Genome of EBV A Tselis, HB Jenson. Epstein-Barr virus 2006. pp 22, Figure 1

Meyers C. 2007 AIDS-Associated Viral Oncogenesis, pp 143 Figure 1

Latent Infection A Arvin et al, Human Herpesvirus. 2007. pp 380. Fig. 24. 1.

Latent Infection A Tselis, HB Jenson. Epstein-Barr virus 2006. pp 24

Potential Mechanism n n Burkitt Lymphoma EBNA-1 cooperate with cmyc ? Deregulate c-myc expression ARF – p 53 pathway? http: //www. benbest. com/he alth/cancer. html

Potential Mechanism n DLBCL : LMP-1 NFκB, JNK, p 38 pathway ? Knockdown LMP-1 from AIDS-DLBLC cell lines apoptosis AIDS-DLBCL : Monoclonal Post-transplant DLBCL : mono/oligo/polyclonal Potential genetic damage ? A Carbone et al, Blood. 2009; 113: 1213 -1224

JNK Pathway NF-κB Pathway http: //www. abgab. com

EBV, HIV and NHL A Carbone et al, Blood. 2009; 113: 1213 -1224

Kaposi Sarcoma-associated Herpesvirus

Kaposi Sarcoma-associated Herpesvirus Chang et al. Identification of Herpesvirus-Like DNA Sequences in AIDS-Associated Kaposi's Sarcoma Science 1994, 2669(5192): 1865 -1869. Subfamily Gammaherpesvirinae Genus Rhadinovirus n Formal Name: Human herpesvirus 8 / HHV-8

Genome of KSHV A Carbone et al, Blood. 2009; 113: 1213 -1224

Target Cells of KSHV n n n n Not yet fully characterized B-cells: peripheral blood, primary effusion lymphomas (PEL), body-cavity based B-cell lymphomas (BCBL), multicentric Castleman’s disease (MCD), Flat endothelial cells: vascular spaces of Kaposi’s sarcoma (KS) lesions, Typical KS Spindle Cells CD 45+/CD 68+ Monocytes in KS Keratinocytes Epithelial Cells

Transmission of KSHV n Sexual transmission n Mother-to-child transmission n Salivary transmission

B Damania, JM Pipas. DNA Tumor Viruses 2009

Seroepidmeiology n n n No gold-standard of antibody test Heterogeneity between different assays ORF 73 / LANA Africa with 30– 60% 3 to 10% in United States and Western Europe 4– 35% Italy and Greece (Mediterranean area with higher incidence rates for classical or transplant-associated KS).

Seroepidmeiology anti-LANA seropositivity approximately 80% of KS less than 5% of non-male-homosexual adults in the USA or Northern Europe (i. e. , specificity of at least 95%) (Kedes et al. , 1996; Gao et al. , 1996 a, b; Simpson et al. , 1996).

Potential Mechanism n Promotion of Cellular Growth and Survival Chromosome Instability Suppress p 53, p. Rb LANA-1, LANA-2, v. IRF-1 Accelerate Cellular Proliferation v. Cyclin Promote Cell Survival v. GPCR, v. FLIP – NFκB pathway Induce growth factors IL-6, IL-8, VEGF etc.

p 53 Pathway www. abgab. com

Cyclins and Cell Cycle Regulation www. abgab. com

Potential Mechanism n n Regulation of Angiogensis (in KS-like lesions) Immune Modulation Passive Strategy de novo Infection: manipulating cytokine regulatory network

KSHV, HIV and NHL A Carbone et al, Blood. 2009; 113: 1213 -1224

Differential Diagnosis of Effusion Lymphoma A Carbone et al, Blood. 2009; 113: 1213 -1224

Louis M. Staudt, NEJM 2006, 354(23): 2431 -42

Epidemiologic Issues ? n n n Heterogeneity between different ethnics : Caucasian Vs. Mongolia ? Prevalence of EBV and KSHV latent infection Any prevention or intervention ? Other Viruses Polyomavirus SV 40 ?

Thank You !