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Submitted by Cleide Dantas (cleidedantas@ufpa.br) on 2014-02-10T15:42:43Z No. of bitstreams: 2 license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) Dissertacao_DeteccaoGenomaVirus.pdf: 1156523 bytes, checksum: adbfd249282c1c9bfd93eb1f89898b80 (MD5) / Approved for entry into archive by Ana Rosa Silva (arosa@ufpa.br) on 2014-04-10T14:09:30Z (GMT) No. of bitstreams: 2 Dissertacao_DeteccaoGenomaVirus.pdf: 1156523 bytes, checksum: adbfd249282c1c9bfd93eb1f89898b80 (MD5) license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) / Made available in DSpace on 2014-04-10T14:09:30Z (GMT). No. of bitstreams: 2 Dissertacao_DeteccaoGenomaVirus.pdf: 1156523 bytes, checksum: adbfd249282c1c9bfd93eb1f89898b80 (MD5) license_rdf: 23898 bytes, checksum: e363e809996cf46ada20da1accfcd9c7 (MD5) Previous issue date: 2010 / O vírus de Epstein Barr (EBV) é o agente causador da mononucleose infecciosa e está associado com várias desordens proliferativas malignas tais como: linfoma de Burkitt, linfoma de Hodgkin e linfomas não Hodgkin. Um total de 118 casos de linfomas diagnosticados no Hospital Ofir Loyola no período de 1996 e 2005 foram analisados no Instituto Evandro Chagas, Ananindeua, Brasil; com o objetivo de detectar o genoma do EBV mediante a identificação dos genes EBER 1 e EBNA1 em casos de doença de Hodgkin. Os espécimes parafinizados foram analisados por hibridização in situ (gene EBER 1) e PCR em tempo real (EBNA 1). Do total, 61% (72/118) dos pacientes eram do sexo masculino e 39% (46/118) do sexo feminino com faixa etária variando entre 3- 98 anos. Sessenta e cinco (55%) foram diagnosticados como doença de Hodgkin e cinqüenta e três (45%) como linfomas não-Hodgkin. O EBV foi identificado nas células Reed Sternberg e variantes em 76,9% (50/65) dos casos de linfoma de Hodgkin com idade média de 28,3 anos (variação, 2-84 anos). Os subtipos histológicos de casos EBV-positivos foram o seguinte: esclerose nodular em 50% (25/50), celularidade mista em 28% (14/50), depleção linfocitária em 14% (7/50) e predominância linfocitária em 8% (4/50). O DNA do EBV foi detectado em 53% (26/49) com um coeficiente de regressão para a curva padrão de 0,99. Este estudo foi a primeira descrição do vírus de Epstein Barr em casos de doença de Hodgkin na região Norte do Brasil; reforçando a hipótese de que o EBV seja um co-fator no processo de transformação neoplásica em conjunto com a predisposição genética e imunidade do paciente, justificando a condução de estudos posteriores a nível molecular. / EBV is the causative agent of infectious mononucleosis and is associated with several malignant proliferative disorders such as Burkitt’s lymphoma, Hodgkin’s lymphoma, some B and T cell non-Hodgkin’s lymphomas. A total of 118 cases of lymphomas diagnosed between 1996 and 2005 were obtained from Instituto Ofir Loyola and analyzed at the Instituto Evandro Chagas, Ananindeua, Brazil. The main objective of the study was to assess the association of Hodgkin’s disease subtypes with sex, age, geographic origin and to determine the prevalence of EBER 1 gene and EBNA 1 gene in cases of Hodgkin´s disease. The EBV antigens using EBER 1 probe in situ hybridization (HIS) and real time quantitative PCR EBV DNA were detected in forty-nine and which were compared with HIS. From the total were obtained 61% (72/118) were male and 39% (46/118) female; patient age ranged from 3 to 98 years. Sixty-five (55%) were diagnosed as having Hodgkin´s disease and fifty-three (45%) were non- Hodgkin´s malignant lymphomas. EBV was identified in the Reed-Sternberg cells and variants in 77% (50/65) of Hodgkin´s disease cases, the median age were 28.3 years (range, 2-84). The histologic subtypes of EBV-positive cases were as follows: nodular sclerosis in 50% (25/50), mixed cellularity in 28% (14/50), lymphocyte depletion in 14% (7/50) and lymphocyte predominance in 8% (4/50). We detected EBV DNA in 53% (26/49) with a coefficient of regression for the standard curve of a minimum of 0.99. These results were the first demonstration of the role of Epstein Barr virus in cases of Hodgkin diseases in northern Brazil and are consistent with the hypothesis that the presence of EBV during neoplasic transformation could be are additional cofactor acting together with both genetic predisposition and immunity of the patient. Further and broader studies are needed in the Amazon region to clarify the relationship between EBV and Hodgkin´s disease.

Viruses are known to be associated with 20% of human cancers. Epstein Barr virus (EBV) in particular is the first virus associated with human cancers. Here, we computationally detect EBV and explore the effects of this virus across cancers by taking advantage of the fact that EBV microRNAs (miRNAs) and Epstein Barr virus small RNAs (EBERs) are expressed at all viral latencies. We identify and characterize two sub-populations of EBV positive tumors: those with high levels of EBV miRNA and EBERS expression and those with medium levels of expression. Based on principal component analysis (PCA) and hierarchical clustering of viral miRNAs across all samples we observe a pattern of expression for these EBV miRNAs which is correlated with both the tumor cell type (B cell versus epithelial cell) and with the overall levels of expression of these miRNAs. We further investigated the effect of the levels of EBV miRNAs with the overall survival of patients across cancers. Through Kaplan Meier survival analysis we observe a significant correlation with levels of EBV miRNAs and lower survival in adult AML patients. We also designed a machine learning model for risk assessment of EBV in association with adult AML and other clinical factors. Our next aim was to identify targets of EBV miRNAs, hence, we used a combination of previously known methodologies for miRNA target detection in addition to a multivariable regression approach to identify targets of these viral miRNAs in stomach cancer. Finally, we investigate the variations across EBV subtype specific EBNA3C gene which interacts with the host immune system. Preliminary data suggests potential regional variations plus higher pathogenicity of subtype 1 in comparison to subtype 2 EBV. Overall, these studies further our understanding of how EBV manipulates the tumor microenvironment across cancer subtypes.

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