Epidemiology and Natural History of Cancer-Associated Viruses

癌症相关病毒的流行病学和自然史

• 批准号: 8938248
• 负责人: SAM M MBULAITEYE
• 金额: $ 337.92万
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8938248
• 关键词: AIDS population; Acquired Immunodeficiency Syndrome; Adolescent; Adrenal Cortex Hormones; Adult; African Burkitt' s lymphoma; Age; Alleles; Antibodies; Antigens; Anus; Biological; Biological Assay; Biological Markers; Breast; Bronchi; Burkitt Lymphoma; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; Cancer Etiology; Case-Control Studies; Categories; Cells; Central Nervous System Lymphoma; Child; Childhood; Clinical; Cohort Studies; Collaborations; DNA Nucleotidylexotransferase; Data; Dermal; Detection; Development; Diabetes Mellitus; Diagnosis; Diagnostic Neoplasm Staging; Disease; Elderly; Enrollment; Epidemiology; Extramural Activities; Falciparum Malaria; Fostering; France; General Population; Genetic Variation; Genotype; Geographic state; Ghana; HIV; Haplotypes; Head and Neck Cancer; Hepatitis C virus; Histopathology; Hodgkin Disease; Hospitals; Human; Human Herpesvirus 8; Human T-lymphotropic virus 1; Immune; Immunity; Incidence; Infection; Infectious Agent; Interleukin-10; Island; Kaposi Sarcoma; Laboratories; Laboratory Procedures; Larynx; Link; Liver; Lung; Lymphoma; Malaria; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Malignant neoplasm of liver; Malignant neoplasm of lung; Malignant neoplasm of penis; Malignant neoplasm of prostate; Malignant neoplasm of testis; Measures; Merkel Cells; Merkel cell carcinoma; Methods; Natural History; Neurodegenerative Disorders; Neuroendocrine Cell; Non-Burkitt' s Lymphoma; Non-Hodgkin' s Lymphoma; Oncornaviruses; Oral cavity; Organ Transplantation; Parasites; Pathology; Patients; Persons; Pharyngeal structure; Plasmodium falciparum; Polyomavirus; Population; Prevalence; Proteins; Research; Resources; Retinoblastoma Genes; Risk; Risk Factors; Role; Saliva; Satellite Viruses; Sicily; Smoking; Soil; Specimen; Staining method; Stains; Tanzania; Time; Tissue Fixation; Tissue Microarray; Tongue; Tumor Tissue; Uganda; United States; Viral; Viral Load result; Virus; aged; antiretroviral therapy; cancer prevention; cancer risk; cancer therapy; case control; clinical Diagnosis; cohort; large cell Diffuse non-Hodgkin' s lymphoma; malignant breast neoplasm; malignant stomach neoplasm; men; multidisciplinary; neoplastic cell; novel; penis; peripheral blood; population based; prospective; reconstitution; time interval; transmission process; tumor; volcano

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 strategiesUsing 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.

该项目由多项重叠的、综合的、多学科的基于人群的队列和/或病例对照研究组成，以量化致癌病毒（致癌病毒）与相关癌症之间的关联。 研究重点是免疫改变、感染和癌症风险的作用，包括BL、NHL、霍奇金淋巴瘤、卡波西肉瘤、肺癌、宫颈癌、头颈癌、睾丸癌、乳腺癌、阴茎癌、和胃癌。生物样本（外周血、唾液、肿瘤组织），如果有的话，用于测量感染因子的负载，包括 HIV、HTLV-I/-II、HCV 和 KSHV，也称为 HHV8、病毒因子的遗传变异或宿主来表征生物标志物与癌症的关联。 对美国 15 年（1991-2005 年）艾滋病和非艾滋病定义癌症风险的分析已经完成。美国艾滋病人口从 1991 年的 96,179 人增加到 2005 年的 413,080 人，增加了四倍。增长的主要原因是 40 岁或以上的人。艾滋病人群中约有 79 656 例癌症发生。艾滋病定义的癌症数量减少了三倍多，从 1991 年的 34,587 例减少到 2005 年的 10,325 例；趋势.001）。相反，在同一时期，非艾滋病定义的癌症数量增加了大约三倍（3193 例癌症增加到 10,059 例；Ptrend .001）。肛门癌（206 至 1564 例癌症）、肝癌（116 至 583 例癌症）、前列腺癌（87 至 759 例癌症）、肺癌（875 至 1882 例癌症）和霍奇金淋巴瘤（426 至 897 例癌症）的癌症数量。 2004 年至 2007 年间，在美国 34 个州仅感染艾滋病毒的人群中，估计发生了 2191 例非艾滋病定义的癌症，其中包括 454 例肺癌、166 例乳腺癌和 154 例肛门癌。 这种日益增长的负担需要有针对性的癌症预防和治疗策略根据美国艾滋病毒/艾滋病癌症匹配研究，在 567、865 名艾滋病毒/艾滋病患者中，BL 发病率在儿科和成人/老年期出现了两个特定年龄的发病率高峰，并随着年龄的增长而下降。 CD4淋巴细胞计数。与非 BL NHL 相比，BL 的双峰峰值表明非累积危险因素在不同年龄的影响。对 1980-2007 年美国艾滋病患者中发生的艾滋病定义的恶性肿瘤的比例进行了分析完全的。 1980-2007年间，83,252例KS病例中的约82%、351,618例DLBCL病例中的6.0%、17,307例伯基特淋巴瘤病例中的20%、27,265例中枢神经系统淋巴瘤病例中的27%以及375,452例宫颈癌病例中的0.42%发生在艾滋病患者中。艾滋病患者中 KS 和 AIDS 定义的 NHL 比例在 1990 年代初达到顶峰（1990-1995 年：KS 为 90%，DLBCL 为 10%，伯基特淋巴瘤为 28%，中枢神经系统淋巴瘤为 48%，随后下降了 70%）。 KS，DLBCL 为 5%，BL 为 21%，CNS 淋巴瘤为 13%。随着时间的推移，艾滋病患者中患宫颈癌的比例从 1980 年至 1991 年的 0.11% 增加到 2001 年至 2007 年的 0.71%。与一般人群相比，艾滋病患者患前列腺癌的风险降低了 50%。 PSA 时代和早期癌症。一项关于 HIV 环境中霍奇金淋巴瘤 (HL) 发病率与免疫重建的研究已使用以下数据完成来自法国的 64 368 名 HIV 患者中的 187 例霍奇金淋巴瘤风险与开始联合抗逆转录病毒治疗 (cART) 后的时间间隔有关，在 cART 治疗的第 1-3 个月内风险尤其显着升高（RR 2.95），在几个月内风险降低。 4-6 (RR 1.63)，并且随着使用时间的延长而无效 (RR 1.00)，CD4 计数与霍奇金淋巴瘤风险密切相关。 50-99 CD4 细胞/毫米。开始 cART 后不久，霍奇金淋巴瘤风险显着增加，这在很大程度上可以通过 CD4 计数来解释。使用美国 HACM 中 263 254 名患有艾滋病的成人和青少年（1980-2004 年）的数据，我们发现两种主要艾滋病的风险升高：定义癌症：卡波西肉瘤（SIR，第 3-5 年的 5321 和 1347，以及分别为 6-10）和非霍奇金淋巴瘤（SIR，32 和 15）以及所有非艾滋病定义癌症的综合（SIR，分别为 3-5 年和 6-10 年的 1.7 和 1.6）以及霍奇金淋巴瘤以及口腔和/或咽、舌、肛门、肝癌、喉、肺癌和/或支气管的癌症，以及在来自乌干达、加纳和坦桑尼亚的 2,602 例非洲伯基特淋巴瘤病例中，年龄特异性疟疾生物标志物（患病率、负荷量和基因型数量）与恶性疟原虫疟疾寄生虫的混合基因型数量相关，但与患病率无关或寄生虫负载。一项研究旨在评估通过外部病理学审查诊断评估的伯基特淋巴瘤临床和局部病理学诊断的准确性，并了解乌干达一家医院资源有限的情况下组织病理学实践的局限性。当地病理实验室程序不一致且欠佳，尤其是组织固定。在 88 例临床推测的 BL 病例中，对 63 例进行了审查，但只有 75% 得到证实。经当地病理确诊的患者中，确诊率为82%。 由于纳入具有相似临床表现的其他疾病，BL 临床诊断的准确性降低。一项利用加纳的数据调查恶性疟原虫 (Pf) 疟疾在伯基特淋巴瘤 (BL) 中的保护性免疫作用的研究已经完成。病例是1965-1994年间在加纳登记的患有伯基特淋巴瘤的儿童，对照是与病例同村的健康儿童。使用针对 SE36 抗原的新型抗体测量疟疾免疫力。在病例中观察到的 SE36 滴度低于对照，并且与 Burkitt 淋巴瘤的 OR 增加相关（对于低滴度和中等滴度，分别为 [OR 1.67] 和 OR 1.33，ptrend = 0.002）。一项为期四年的病例对照研究整个西西里岛（其中 cKS 和 KSHV 流行）的经典（非艾滋病）卡波西肉瘤和 KSHV 感染已完成。当前吸烟可显着降低典型 KS 风险，而糖尿病和使用皮质类固醇则可显着且独立地增加该风险。 典型的 KS 也会随着住宅暴露于铬黄土（一种与火山相关的土壤）而增加。 最近在默克尔细胞癌 (MCC) 中发现了默克尔细胞多瘤病毒 (MCPyV)，这是一种临床和病理上异质性的真皮神经内分泌细胞恶性肿瘤。我们开发了组织微阵列 (TMA) 来表征候选肿瘤细胞蛋白的免疫组织化学染色，并开发了定量 PCR 测定法来检测 MCPyV 和测量病毒载量。在 23 个原发性 MCC 肿瘤中的 19 个 (74%) 中检测到 MCPyV，但其中 8 个每 300 个细胞的病毒拷贝数少于 1 个。通过免疫组织化学染色，0.06-1.2 个病毒拷贝/细胞的病毒丰度与视网膜母细胞瘤基因产物 (pRb) 和末端脱氧核糖核苷酸转移酶 (TdT) 的存在直接相关 (p 或 = 0.003)。较高的病毒丰度肿瘤往往与较少的 p53 表达、诊断时较年轻和较长的生存期相关（p 或 = 0.08）。使用多中心艾滋病队列研究 (MACS) 的数据，我们表明携带至少一个副本的IL10 rs1800871 的 T 等位基因（与无拷贝相比）与中枢神经系统引起的淋巴瘤特异性 AIDS-NHL 风险降低相关（CC 与 CT/TT：OR = 0.3；95% CI 0.1, 0.7），但不是系统性的（CC 与 CT/TT：OR = 1.0；95% CI 0.5, 1.9）（异质性 = 0.03）。携带两个拷贝的“低 IL10”单倍型 rs1800896_A/rs1800871_T/rs1800872_A 与淋巴瘤风险降低相关，该风险因拷贝数而异（Ptrend = 0.02）。与私人和学术实验室建立了合作，以促进已知或可能的癌症相关病毒检测方法的开发。