This project consists of several overlapping comprehensive, multidisciplinary population-based cohort and/or case-control studies to quantify the association between cancer-causing viruses (oncoviruses) with linked cancers. The studies focus on the role of the role of immunological alteration, infection and risk for cancer, including BL, NHL, Hodgkin lymphoma, kaposi sarcoma, lung cancer, cervical cancer, head and neck cancer, testicular cancer, breast cancer, penile cancer, and gastric cancer. Biological specimens (peripheral blood, saliva, tumor tissues), when available, are used to measure load of infectious agents, including HIV, HTLV-I/-II, HCV, and KSHV, also called HHV8, genetic variation in viral agents or the host to characterize association of biomarkers with cancer. An analysis of risk for AIDS and non-AIDS-defining cancers in the U.S. covering a 15-year period (1991-2005) was completed. The US AIDS population expanded fourfold from 96,179 in 1991 to 413,080 in 2005. The increases were mostly due to people aged 40 years or older. About 79 656 cancers occurred in the AIDS population. The number of AIDS-defining cancers decreased by more than threefold from 34,587 in 1991 to 10,325 cancers in 2005;Ptrend .001). Conversely, during the same time, the number of non-AIDS-defining cancers increased by approximately threefold (3193 to 10,059 cancers;Ptrend .001). The number of cancers for anus (206 to 1564 cancers), liver (116 to 583 cancers), prostate (87 to 759 cancers), and lung cancers (875 to 1882 cancers), and Hodgkin lymphoma (426 to 897 cancers). In the HIV-only population in 34 US states, an estimated 2191 non-AIDS-defining cancers occurred during 2004-2007, including 454 lung, 166 breast, and 154 anal cancers. This growing burden requires targeted cancer prevention and treatment strategies Using the U.S. HIV/AIDS Cancer Match Study, among 567, 865 persons with HIV/AIDS, BL incidence showed two age-specific incidence peaks during the pediatric and adult/geriatric years and decreased with decreasing CD4 lymphocyte counts. The bimodal peaks for BL, in contrast to non-BL NHL, suggest effects of non-cumulative risk factors at different ages. An analysis of the proportion of AIDS-defining malignancies in the United States occurring in persons with AIDS during 1980-2007 was completed. About 82% of 83,252 KS cases, 6.0% of 351,618 DLBCL cases, 20% of 17,307 Burkitt lymphoma cases, 27% of 27,265 CNS lymphoma cases, and 0.42% of 375,452 cervical cancer cases occurred among persons with AIDS during 1980-2007. The proportion of KS and AIDS-defining NHLs in persons with AIDS peaked in the early 1990s (1990-1995: 90% for KS, 10% for DLBCL, 28% for Burkitt lymphoma and 48% for CNS lymphoma and then declined 70% for KS, 5% for DLBCL,21% for BL, and 13% for CNS lymphoma. The proportion of cervical cancers in persons with AIDS increased over time from 0.11% in 1980-1991 to 0.71% in 2001-2007. Prostate cancer risk was decreased by 50% among men with AIDS compared with the general population. This deficit was limited to the PSA era and early stage cancers. A study of Hodgkin lymphoma (HL) incidence with immune reconstitution in the HIV settng was completed using data on 187 Hodgkin lymphoma cases among 64 368 HIV patients from France. Hodgkin lymphoma risk was related to time intervals after combination antiretroviral therapy (cART) initiation. Risk was especially and significantly elevated in months 1-3 on cART (RR 2.95), lower in months 4-6 (RR 1.63), and null with longer use (RR 1.00). CD4 count was strongly associated with Hodgkin lymphoma risk at 50-99 CD4 cells/mm. Hodgkin lymphoma risk increased significantly soon after cART initiation, which was largely explained by the CD4 count. Using data from 263 254 adults and adolescents with AIDS (1980-2004) the U.S. HACM, we showed that risk was elevated for the 2 major AIDS-defining cancers: Kaposi sarcoma (SIRs, 5321 and 1347 in years 3-5 and 6-10, respectively) and non-Hodgkin lymphoma (SIRs, 32 and 15) and for all non-AIDS-defining cancers combined (SIRs, 1.7 and 1.6 in years 3-5 and 6-10, respectively) and for Hodgkin lymphoma and cancers of the oral cavity and/or pharynx, tongue, anus, liver, larynx, lung and/or bronchus, and penis. Among 2,602 cases of African Burkitt lymphoma from Uganda, Ghana, and Tanzania, age-specific malaria biomarkers (prevalence, load, and number of genotypes) were correlated with the number of mixed genotypes of P. falciparum malaria parasites, but not prevalence or load of parasites. A study to assess the accuracy of the clinical and the local pathology diagnosis of Burkitt lymphoma as assessed by an outside pathology review diagnosis and to understand the limitations on histopathology practice in a resource-constrained setting at 1 hospital in Uganda. Local pathology laboratory procedures were inconsistent and suboptimal, especially for tissue fixation. Of 88 clinically presumed BL cases, 63 were reviewed and only 75% were confirmed. Of those locally diagnosed by pathology, 82% were confirmed. Accuracy of clinical diagnosis of BL was reduced by inclusion of other diseases with similar clinical presentations. A study to investigate the role of protective immunity to Plasmodium falciparum (Pf) malaria in Burkitt lymphoma (BL) using data from Ghana was completed. Cases were children with Burkitt lymphoma enrolled in Ghana during 1965-1994 and controls were healthy children from the same village as the cases . Malaria immunity was measured using a novel antibody to SE36 antigen. Lower titers of SE36 were observed in cases than controls and were associated with increased OR for Burkitt lymphoma ([OR 1.67] and OR 1.33, for low and medium titers, respectively, ptrend = 0.002). A four-year case-control study of classic (non-AIDS) Kaposi sarcoma and KSHV infection throughout the island of Sicily (where cKS and KSHV are endemic) was completed. Classic KS risk was significantly reduced with current smoking, and it was significantly and independently increased with diabetes and use of corticosteroids. Classic KS also was increased with residential exposure chromic luvisols, a soil associated with volcanoes. Merkel cell polyomavirus (MCPyV) was recently discovered in Merkel cell carcinoma (MCC), a clinically and pathologically heterogeneous malignancy of dermal neuroendocrine cells. We developed a tissue microarray (TMA) to characterize immunohistochemical staining of candidate tumor cell proteins and a quantitative PCR assay to detect MCPyV and measure viral loads. MCPyV was detected in 19 of 23 (74%) primary MCC tumors, but 8 of these had less than 1 viral copy per 300 cells. Viral abundance of 0.06-1.2 viral copies/cell was directly related to presence of retinoblastoma gene product (pRb) and terminal deoxyribonucleotidyl transferase (TdT) by immunohistochemical staining (p or = 0.003). Higher viral abundance tumors tended to be associated with less p53 expression, younger age at diagnosis and longer survival (p or = 0.08). Using data from the Multicenter AIDS Cohort Study (MACS), we showed that carriage of at least one copy of the T allele for the IL10 rs1800871 (as compared to no copies) was associated with decreased AIDS-NHL risk specific to lymphomas arising from the CNS (CC vs. CT/TT: OR = 0.3;95% CI 0.1, 0.7) but not systemically (CC vs. CT/TT: OR = 1.0;95% CI 0.5, 1.9) (Pheterogeneity = 0.03). Carriage of two copies of the 'low IL10'haplotype rs1800896_A/rs1800871_T/rs1800872_A was associated with decreased lymphoma risk that varied by number of copies (Ptrend = 0.02). Collaborations with private and academic laboratories were established to foster development of detection methods for known or possible cancer-associated viruses.
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