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; 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.

该项目包括几个重叠的综合，多学科的基于人群的队列和/或病例对照研究，以量化引起癌症的病毒（Oncovires）与链接的癌症之间的关联。这些项目包括HIV-AIDS癌症竞赛（HACM）研究，该研究将约78万人在美国14个州和大都市区域与癌症注册表数据联系起来，以检查HIV感染的个体中的癌症风险和移植癌症（TCM）研究（TCM）研究，该研究将受体的受体与175,000个三个植物的癌症分类数据联系到13个癌症研究中的癌症。此外，关注BL的项目包括加纳BL研究和具有广泛目标的标志研究，以研究感染的作用，包括HIV，对EBV的免疫反应和恶性疟疾疟疾的免疫反应以及对BL病因的遗传易感性。该研究重点是免疫学改变，感染和癌症风险的作用，包括BL，NHL，Hodgkin淋巴瘤，Kaposi肉瘤，肺癌，宫颈癌，头颈癌，睾丸癌，乳腺癌，阴茎癌，阴茎癌和胃癌。生物学标本（外周血，唾液，肿瘤组织）（如果有的话）用于测量包括HIV，EBV和KSHV在内的传染剂负载，也称为HHV8，PF疟疾和病原体A或宿主中的遗传变异，以表征与癌症的生物标志物的缔合。建立了与私人和学术实验室的合作，以促进已知或可能与癌症相关病毒的检测方法的开发。美国HACM的研究提供了持续的证据，表明艾滋病毒对艾滋病毒感染者对癌症风险的强烈和持久影响。使用美国HIV感染和一般人群的癌症发病率，并将Poisson模型应用于连接的HIV和癌症注册表数据，以及从监视，流行病学和最终结果计划数据中，估计有7760（95％置信区间[CI] = 7330至8320）在2010年发生HIV受害者中发生了CANCERS。其中3920次癌症（95％CI = 3480至4470）或50％（95％CI = 48至54％）超出了预期。最常见的多余癌症是非霍奇金的淋巴瘤（NHL; n = 1440多次癌症，过剩88％），Kaposi的肉瘤（KS，n = 910，100％过剩），肛门癌（N = 740，97％过量）和肺癌（N = 440，52％过量）。自AIDS诊断以来，定义艾滋病（即，KS，NHL，宫颈癌）的多余癌症的比例下降（均为.001 p .001）。对于肛门癌，有83％的过量病例发生在与男性发生性关系的男性中，自艾滋病发作以来五年以上的人中有71％。在注射吸毒者中，多余的癌症中有22％是肺癌，16％是肝癌。 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,和肛门生成癌）。可归因于20-29岁年龄段（69％，95％CI 65-72）和与男性发生性关系的男性（48％，95％CI 46-50）的感染分数最高。对HACM数据的进一步分析还表明，与HIV未感染的患者相比，感染HIV的癌症患者的癌症特异性死亡率更高，而不论癌症阶段或接受癌症治疗如何。一项研究，研究了伯基特淋巴瘤（BL）使用加纳数据中保护性免疫对恶性疟原虫（PF）疟疾的作用的研究。病例是1965年至1994年在加纳招收的伯基特淋巴瘤儿童，对照组是与病例同一村庄的健康儿童。使用对HRP-II的新抗体（一种被认为标志着最近疟疾的抗原）和PF SE36（被认为具有保护性的抗原）和384例匹配的对照来测量疟疾免疫力。 BL与HRP-II血清阳性呈正相关（OR = 1.60; 95％CI 1.08-2.36），并与SE36的血清阳性率（OR = 0.37; 95％CI = 0.21-0.64）反向相关。 此外，与HRP-II-SeroneNogative和SE36-孔阳性响应者相比，HRP-II - 阳性和SE36-副反应者的BL风险高21倍（95％CI = 5.8-74），而SE36-副反应者则高21倍（SE36-Seronegative响应者），这表明最近有没有保护性抗体的Malararia证据表明，这种疾病最高的抗体是最高风险的。使用广泛研究所开发的敏感和特定的24 SNP PF分子 - 巴尔卡模数阵列，马拉维的BL病例比马拉维的非BL癌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133.1 [SE = 7.7]，T检验P = 0.036）。这表明，马拉维BL的PF疟疾感染的遗传多样性评分之间存在正相关，从而阐明了感染如何驱动定义癌症（例如BL）的艾滋病风险的新启示。在关注BL肿瘤组织的研究中，在转录因子TCF3（E2A）（其阴性调节剂ID3）中发现了研究新突变。 TCF3/ID3中的突变存在于大约70％的HIV相关和零星BL和40％的流行BL中，而CCND3中的突变代码为驱动细胞周期进展的蛋白质中，38％的孢子虫BL中存在，但仅在仅1.8％的地方性BL中存在。 这些结果表明，BL发病机理的新途径可以针对BL的更简单和毒性治疗的有理设计。为了了解EBV在美国BL中的作用，通过组织微阵列（TMA）研究了SEER残留组织存储库（SRTR）的91个确认的BL组织。大约三分之一的BL病例是EBV肿瘤阳性。与白人相比，与白人相比，与白人相比，EBV阳性最低，黑人/西班牙裔的阳性率更高，与HIV阴性相比，HIV阳性较高。 这些结果表明，EBV阳性和EBV负BL是不同类型的类型，其分布在不同的人口组中是不同的。