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: 10007424
• 负责人: SAM M MBULAITEYE
• 金额: $ 53.21万
• 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/10007424
• 关键词: 20 year old; Acquired Immunodeficiency Syndrome; Affect; African Burkitt' s lymphoma; Age; Anogenital cancer; Antibodies; Antigens; Biological; Biological Markers; Breast; Burkitt Lymphoma; Cancer Etiology; Case-Control Studies; Categories; Cell Cycle Progression; Child; Clinical; Code; Cohort Studies; Collaborations; Comparative Study; Confidence Intervals; Data; Data Analyses; Detection; Development; Diagnosis; Disease; Enrollment; Epidemiology; Etiology; Extramural Activities; Falciparum Malaria; Fostering; General Population; Genetic Predisposition to Disease; Genetic Variation; Ghana; Goals; HIV; HIV Seronegativity; HIV Seropositivity; HIV diagnosis; Head and Neck Cancer; Helicobacter pylori; Hepatitis B; Hepatitis C virus; Hispanics; Hodgkin Disease; Human; Human Herpesvirus 4; Human Herpesvirus 8; Human Papillomavirus; Immune response; Immunity; Immunologics; Incidence; Individual; Infection; Infectious Agent; Injecting drug user; Institutes; Kaposi Sarcoma; Laboratories; Light; Link; Liver; Lymphoma; Malaria; Malawi; 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 testis; Measures; Methods; Modeling; Molecular; Mutation; Natural History; Non-Burkitt' s Lymphoma; Non-Hodgkin' s Lymphoma; Oncornaviruses; Organ Transplant Research; Pathogenesis; Pathway interactions; Patients; Persons; Plasmodium falciparum; Population; Population Attributable Risks; Privatization; Proteins; Residual state; Risk; Role; SEER Program; Saliva; Satellite Viruses; Specimen; Stomach; T cell factor 3; TCF3 gene; Testing; Time; Tissue Microarray; Tissues; Transplant Recipients; Tumor Tissue; United States; Virus; age group; cancer risk; cancer therapy; cancer transplantation; comparative; data registry; design; disorder risk; experience; high risk; infection risk; malaria infection; malignant breast neoplasm; malignant stomach neoplasm; men who have sex with men; metropolitan; mortality; multidisciplinary; neoplasm registry; novel; pathogen; peripheral blood; population based; prospective; repository; seropositive; tumor; viral transmission

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 projects include the HIV-AIDS Cancer Match (HACM) Study that links some 780,000 people with HIV-AIDS in 14 U.S. states and metropolitan regions with cancer registry data to examine cancer risk among HIV-infected individuals and the Transplant Cancer Match (TCM) Study that links some 175,000-transplant recipients to cancer registry data in 13 cancer for comparative studies. In addition, focused projects on BL include the Ghana BL Study and the EMBLEM Study with broad goals to study the role of infections, including HIV, immune responses to EBV and Plasmodium falciparum malaria and genetic susceptibility in the etiology to BL. 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, EBV, and KSHV, also called HHV8, Pf malaria and genetic variation in the pathogens a or the host to characterize association of biomarkers with cancer. Collaborations with private and academic laboratories were established to foster development of detection methods for known or possible cancer-associated viruses. Study of the US HACM provides continuing evidence of strong and durable impact of HIV on cancer risk in HIV infected persons. Using cancer incidence rates for the United States HIV-infected and general populations and applying Poisson models to linked HIV and cancer registry data and from Surveillance, Epidemiology, and End Results program data, an estimated 7760 (95% confidence interval [CI] = 7330 to 8320) cancers occurred in 2010 among HIV-infected people. Of these, 3920 cancers (95% CI = 3480 to 4470) or 50% (95% CI = 48 to 54%) were in excess of expected. The most common excess cancers were non-Hodgkin's lymphoma (NHL; n = 1440 excess cancers, occurring in 88% excess), Kaposi's sarcoma (KS, n = 910, 100% excess), anal cancer (n = 740, 97% excess), and lung cancer (n = 440, 52% excess). The proportion of excess cancers that were AIDS defining (ie, KS, NHL, cervical cancer) declined with age and time since AIDS diagnosis (both P .001). For anal cancer, 83% of excess cases occurred among men who have sex with men, and 71% among those living five or more years since AIDS onset. Among injection drug users, 22% of excess cancers were lung cancer, and 16% were liver cancer. An analysis of risk of cancers associated with infection persons diagnosed HIV in the United States in 2008 showed that 40% (95% CI 39-42) of the cancers are attributable to an infection, particularly Kaposi sarcoma herpes virus, Epstein-Barr virus, and human papillomavirus, which together were responsible for 90% of the new cancers (mainly Kaposi sarcoma, lymphomas, and ano-genital cancers). The infection attributable fraction was highest in the age group 20-29 years (69%, 95% CI 65-72) and in men who have sex with men (48%, 95% CI 46-50). Further analysis of data from HACM also showed that HIV-infected patients with cancer experienced higher cancer-specific mortality than in HIV-uninfected patients, regardless of the cancer stage or receipt of cancer treatment. 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 novel antibodies to HRP-II (an antigen believed to mark recent malaria) and Pf SE36 (thought to be protective) in 354 cases and 384 matched controls. BL was positively associated with HRP-II seropositivity (OR = 1.60; 95% CI 1.08-2.36) and inversely associated with SE36 seropositivity (OR = 0.37; 95% CI = 0.21-0.64) after control for confounding factors. Furthermore, BL risk was 21 times higher (95% CI = 5.8-74) in HRP-II-seropositive and SE36-seronegative responders compared with HRP-II-seronegative and SE36-seropositive responders, suggesting that individuals with evidence of recent malaria who lack protective antibodies are at highest risk for this disease. Using a sensitive and specific 24 SNP Pf molecular-barcode array developed by the Broad Institute, BL cases from Malawi were shown to have greater genetic diversity than non-BL cancers from Malawi (mean genetic diversity score: 153.9 [se=5.8] versus 133.1 [se=7.7], t-test p=0.036). This suggested that there is a positive correlation between genetic diversity score of Pf malaria infection in BL in Malawi, shedding new light on how infections might drive risk for an AIDS defining cancer such as BL. In studies focusing on BL tumor tissues, study novel mutations were discovered in the transcription factor TCF3 (E2A), its negative regulator ID3. The mutations in TCF3/ID3 were present in about 70% of HIV-associated and sporadic BL and 40% of endemic BL, while mutations in CCND3, which codes for proteins that drive cell cycle progression were present in 38% of sporadic BL, but in only 1.8% of endemic BL. These results point to novel pathways for BL pathogenesis, which can be targeted rational design of simpler and less toxic treatment for BL. To understand the role of EBV in BL in the US, 91 confirmed BL tissues from the SEER Residual Tissue Repository (SRTR)were studied by tissue microarray (TMA). About one-third of the BL cases were EBV tumor positive. EBV positivity was lowest in cases aged 20 years and 60 years, higher in Blacks/Hispanics compared to Whites, and higher HIV positive cases compared to those who were HIV negative. These results suggest that EBV positive and EBV negative BL are distinct types whose distribution is different in different demographic groups.

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。这些项目包括艾滋病毒-艾滋病癌症匹配 (HACM) 研究，该研究将美国 14 个州和大都市地区约 780,000 名艾滋病毒感染者与癌症登记数据联系起来，以检查艾滋病毒感染者的癌症风险，以及移植癌症匹配 (TCM)研究将约 175,000 名移植受者与 13 种癌症的癌症登记数据联系起来进行比较研究。此外，关于 BL 的重点项目包括加纳 BL 研究和 EMBLEM 研究，其广泛目标是研究感染的作用，包括 HIV、对 EBV 和恶性疟原虫疟疾的免疫反应以及 BL 病因学中的遗传易感性。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）用于测量传染源的负荷，包括 HIV、EBV 和 KSHV（也称为 HHV8）、Pf 疟疾以及病原体或宿主的遗传变异，以表征生物标志物与癌症的关联。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。美国 HACM 的研究提供了持续的证据，证明艾滋病毒对艾滋病毒感染者的癌症风险有强大而持久的影响。使用美国 HIV 感染者和普通人群的癌症发病率，并应用泊松模型关联 HIV 和癌症登记数据以及监测、流行病学和最终结果计划数据，估计为 7760（95% 置信区间 [CI] = 7330）到 8320) 2010 年艾滋病毒感染者中发生了癌症。其中，3920 种癌症（95% CI = 3480 至 4470）或 50%（95% CI = 48 至 54%）超出预期。最常见的过量癌症是非霍奇金淋巴瘤（NHL；n = 1440 过量癌症，过量发生 88%）、卡波西肉瘤（KS，n = 910，过量 100%）、肛门癌（n = 740，过量 97%） ）和肺癌（n = 440，超出 52%）。艾滋病定义的过量癌症（即 KS、NHL、宫颈癌）的比例随着年龄和艾滋病诊断后时间的推移而下降（均为 P < .001）。对于肛门癌，83% 的超额病例发生在男男性行为者中，71% 的病例发生在艾滋病发病五年或以上的患者中。在注射吸毒者中，过量癌症中22%是肺癌，16%是肝癌。 2008 年对美国诊断出 HIV 感染者相关癌症风险的分析表明，40% (95% CI 39-42) 的癌症可归因于感染，特别是卡波西肉瘤疱疹病毒、EB 病毒、和人乳头瘤病毒，它们共同导致了 90% 的新癌症（主要是卡波西肉瘤、淋巴瘤和肛门生殖器瘤）癌症）。感染归因分数在 20-29 岁年龄组（69%，95% CI 65-72）和男男性行为者中最高（48%，95% CI 46-50）。对 HACM 数据的进一步分析还表明，无论癌症分期或接受癌症治疗如何，感染 HIV 的癌症患者比未感染 HIV 的患者的癌症特异性死亡率更高。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 年至 1994 年期间在加纳登记的患有伯基特淋巴瘤的儿童，对照是来自与病例同一村庄的健康儿童。在 354 例病例和 384 名匹配对照中，使用针对 HRP-II（一种被认为标志着近期疟疾的抗原）和 Pf SE36（被认为具有保护性）的新型抗体测量了疟疾免疫力。在控制混杂因素后，BL 与 HRP-II 血清阳性呈正相关（OR = 1.60；95% CI = 1.08-2.36），与 SE36 血清阳性呈负相关（OR = 0.37；95% CI = 0.21-0.64）。 此外，与 HRP-II 血清阴性和 SE36 血清阳性应答者相比，HRP-II 血清阳性和 SE36 血清阴性应答者的 BL 风险高 21 倍（95% CI = 5.8-74），这表明近期有疟疾证据的个体缺乏保护性抗体的人患这种疾病的风险最高。使用 Broad Institute 开发的敏感且特异的 24 SNP Pf 分子条形码阵列，显示马拉维的 BL 病例比马拉维的非 BL 癌症具有更大的遗传多样性（平均遗传多样性得分：153.9 [se=5.8] 对比 133.1） [se=7.7]，t 检验 p=0.036）。这表明马拉维 BL 中 Pf 疟疾感染的遗传多样性评分之间存在正相关性，这为了解感染如何增加 BL 等艾滋病定义癌症的风险提供了新的线索。在针对 BL 肿瘤组织的研究中，研究人员在转录因子 TCF3 (E2A)（其负调节因子 ID3）中发现了新的突变。 TCF3/ID3 突变存在于约 70% 的 HIV 相关性和散发性 BL 中，以及 40% 的地方性 BL 中，而编码驱动细胞周期进展的蛋白质的 CCND3 突变存在于 38% 的散发性 BL 中，但仅占地方性 BL 的 1.8%。 这些结果指出了 BL 发病机制的新途径，可以有针对性地合理设计更简单、毒性更低的 BL 治疗方法。为了了解 EBV 在美国 BL 中的作用，通过组织微阵列 (TMA) 对来自 SEER 残留组织存储库 (SRTR) 的 91 个经证实的 BL 组织进行了研究。大约三分之一的 BL 病例 EBV 肿瘤呈阳性。 20 岁和 60 岁人群的 EBV 阳性率最低，黑人/西班牙裔的阳性率高于白人，而 HIV 阳性病例的阳性率高于 HIV 阴性者。 这些结果表明，EBV 阳性和 EBV 阴性 BL 是不同的类型，其在不同人口群体中的分布不同。