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: 7966670
• 负责人: SAM M MBULAITEYE
• 金额: $ 248.4万
• 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/7966670
• 关键词: AIDS diagnosis; AIDS related cancer; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adrenal Cortex Hormones; Adult; Age; Alleles; Arts; Biological; Biological Markers; Blood; Blood Platelets; Breast; Burkitt Lymphoma; C-reactive protein; CD4 Lymphocyte Count; CD4 Positive T Lymphocytes; CXC Chemokines; Calendar; Cancer Etiology; Candidate Disease Gene; Carcinoma in Situ; Case-Control Studies; Categories; Cell Count; Cells; Cellularity; Cervix Uteri; Clinical; Clinical Management; Clonality; Collaborations; Consensus; DNA; Data Analyses; Detection; Development; Diabetes Mellitus; Disease; Enrollment; Epidemiology; Equation; Extramural Activities; Fostering; Gene Expression; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; HIV; HIV-1; Haplogroup; Head and Neck Cancer; Hemoglobin; Hemophilia A; Hepatitis B Virus; Hepatitis C virus; Highly Active Antiretroviral Therapy; Hodgkin Disease; Human; Human Herpesvirus 4; Human Herpesvirus 8; Human T-lymphotropic virus 1; IL10 gene; IL18 gene; IgE; Immunoglobulins; Immunosuppression; In Situ; Incidence; Individual; Infection; Infectious Agent; Interleukin-10; Interleukin-13; Interleukin-6; Island; Jamaica; Kaposi Sarcoma; Laboratories; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Malignant neoplasm of lung; Malignant neoplasm of penis; Malignant neoplasm of testis; Malignant neoplasm of vulva; Measures; Merkel cell carcinoma; Methods; Mitochondria; Modeling; Multicenter Hemophilia Cohort Study; Natural History; Neuraxis; Neurodegenerative Disorders; Neurosecretory Systems; Non-Hodgkin' s Lymphoma; Odds Ratio; Oncogenes; Oncornaviruses; Organ Transplantation; Oropharyngeal; Patients; Pattern; Persons; Polyomavirus; Population; Population Decreases; Principal Component Analysis; Procedures; Registries; Relative Risks; Reporting; Research; Retinoblastoma; Risk; Role; Saliva; Sampling; Satellite Viruses; Sclerosis; Serum; Serum Markers; Sicily; Single Nucleotide Polymorphism; Skin Cancer; Smoking; Soil; Specimen; T-Cell Leukemia; T-Lymphocyte; Time; Tumor Tissue; Vagina; Variant; Vascular Cell Adhesion Molecule-1; Viral; Virus; Vulva; Y Chromosome; base; beta-Chemokines; cancer risk; cohort; follow-up; large cell Diffuse non-Hodgkin' s lymphoma; leukemia/lymphoma; malignant breast neoplasm; malignant stomach neoplasm; men; molecular pathology; multidisciplinary; novel; outcome forecast; penis; peripheral blood; population based; prospective; sex; transmission process; trend; tumor; viral DNA; virology; volcano; web site

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. The Second Multicenter Hemophilia Cohort Study (MHCS-II) enrolled and completed prospective follow-up of more than 2500 HCV-exposed persons with hemophilia. A public website was established (https:mhcs-ii.rti.org) with background information and data analysis procedures. Progression of HIV to AIDS was shown to be associated with mitochondrial and Y chromosome DNA haplogroups and with variants in the APOBEC3B and IL10 genes. Likelihood of hepatitis B virus (HBV) clearance was associated with variants in IL10 and IL20, and likelihood of hepatitis C virus (HCV) clearance was associated with variants in IL18 and immunoglobulin GM alleles. 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. People with HIV/AIDS are at markedly increased risk for Merkel cell carcinoma (MCC), a highly lethal neuroendocrine skin cancer in which a novel polyomavirus (MCPyV) was recently discovered by others. MCC tumors that had little or no detectable MCPyV DNA were found to have high expression of the retinoblastoma oncogene and worse prognosis, compared to MCC tumors with a high level of MCPyV. A consensus group was convened, reporting the state-of-the-art of MCC and MCPyV virology, epidemiology, molecular pathology, and clinical management. Among 395 NHL cases from Jamaica matched by age, sex, calendar-year and HTLV serostatus to 309 controls from the same population, decreased NHL risk was associated with polymorphisms in Interleukin 13 (IL13) Ex4+98A>G (rs20541) odds ratio (OR) AG/AA)=0.62, p=0.006, vascular cell adhesion molecule 1 (VACM1) Ex9+ 14G>A polymorphism (rs1041163) OR [CT] 0.77, OR [CC] 0.35, p for trend =0.007. The associations were stronger in analyses restricted to patients with adult T cell leukemia/lymphoma (ATL) and HTLV-seropositive controls, suggesting that these genes may be etiologically important in the development of ATL Using the U.S. HIV/AIDS Cancer Match Study, among 499,230 persons with HIV/AIDS, the risk of in situ and invasive cancers of the anus, cervix, oropharynx, penis, vagina, and vulva was significantly higher among persons with AIDS compared to the general population. During the highly active antiretroviral therapy (HAART) era (1996-2004), a low CD4 T-cell count was associated with increased risk of invasive anal cancer, invasive cervical cancer, and in situ vagina or vulva cancers. Among men, incidence of in situ and invasive anal cancer was significantly higher during 1996-2004 than 1990-1995 (61% increase for in situ cancers and 104% increase for invasive cancers). Incidence of other cancers was stable over time. These results show that HPV-associated cancer risk is increased among persons with AIDS and rises with increasing immunosuppression. The increasing anal cancer incidence during the HAART era indicates that prolonged survival may be associated with increased risk of certain HPV-associated cancers. In a study of cancer risk in the 4-27 month period following AIDS diagnosis, KS incidence was lower in 1996-2002 (335/ 100,000 person-years) than in 1990-1995 (1839/100,000 person-years), NHL incidence pattern was similar (i.e., 390/100,000 person-years in 1996-2002 and 1066/100,000 person-years in 1990-1995). In 1996-2002, for each decline in CD4 cell count of 50 cells per microliter of blood, KS risk increased by 40%, central nervous system non-Hodgkin lymphoma subtypes by 85%, diffuse large B-cell lymphoma 12%, but n increases were demonstrable for Burkitt lymphoma . Kaposi sarcoma (RR = 0.22, 95% CI = 0.20 to 0.24) and for non-Hodgkin lymphoma (RR = 0.40, 95% CI = 0.36 to 0.44) risks were lower in the period of 1996-2002 than in 1990-1995. In persons with HIV/AIDS (PWHAs), the risk of Hodgkin lymphoma (HL) 4 through 27 months after AIDS onset was significantly higher in 1996 to 2002 than earlier. The incidence in PWAs with 150 to 199 CD4 cells/muL was 53.7 per 10(5) py's, whereas in PWAs with fewer than 50 CD4 cells/muL, it was 20.7 per 10(5) py's (P(trend) = .002). For each HL subtype, incidence decreased with declining CD4 counts, but nodular sclerosing decreased more precipitously than mixed cellularity, thereby increasing the proportion of mixed cellularity HL seen in PWAs. The extent standardized incidence ratio (SIR) may underestimate relative risk (RR) of cancer risk among people with HIV/AIDS (PWHA) in registry-based was investigated using the 3 AIDS-related cancers: KS, central nervous system non-Hodgkin lymphoma (CNS NHL) and cervical cancer. SIRs substantially underestimate RRs for KS and CNS NHL, likely from the exceptionally high relative risk of KS and CNS NHL among PWHA. We measured serum levels in 360 HIV-1-infected individuals of soluble CD23 (sCD23), sCD27, sCD30, interleukin (IL)-6, IL-10, total immunoglobulin E, C-reactive protein, and Epstein-Barr virus DNA load, and genotyped 38 single nucleotide polymorphisms (SNPs) in candidate genes. We used principal component (PC) analysis to summarize inter-individual and longitudinal variation in the serum markers and generalized estimating equations to model the relationship between the first PC and the 38 SNPs. Ten SNP associations with serum levels were statistically significant, of which the strongest were IL13-1112C>T with sCD30, CC chemokine ligand 5 (CCL5)-403G>A with sCD23, and CXC chemokine ligand 12 (CXCL12)+535G>A with IL-10 (all p<0.01). Higher values of the serum marker first PC were associated with CCL5-403A and lower values were related to IL13-1112T. These findings suggest mixed genetic influences on Th2 markers overall, and discordance of Th2 polarization of circulating T-cells and serum levels in HIV-infected subjects. Using samples from the KS clonality and gene expression study, we showed that HHV8 load in cross-sectional peripheral blood was associated with KS progression and, to a lesser extent, with KS burden. Other correlates include low hemoglobin and low platelets. 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。第二次多中心血友病队列研究 (MHCS-II) 入组并完成了对 2500 多名 HCV 暴露的血友病患者的前瞻性随访。建立了一个公共网站（https：mhcs-ii.rti.org），提供背景信息和数据分析程序。研究表明，HIV 发展为 AIDS 与线粒体和 Y 染色体 DNA 单倍群以及 APOBEC3B 和 IL10 基因的变异有关。乙型肝炎病毒 (HBV) 清除的可能性与 IL10 和 IL20 的变异相关，丙型肝炎病毒 (HCV) 清除的可能性与 IL18 和免疫球蛋白 GM 等位基因的变异相关。一项针对整个西西里岛（cKS 和 KSHV 流行）的经典（非艾滋病）卡波西肉瘤和 KSHV 感染的为期四年的病例对照研究已经完成。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。经典 KS 也会随着住宅暴露于铬软土（一种与火山有关的土壤）而增加。艾滋病毒/艾滋病患者患默克尔细胞癌 (MCC) 的风险显着增加，默克尔细胞癌是一种高度致命的神经内分泌皮肤癌，其他人最近发现了一种新型多瘤病毒 (MCPyV)。与具有高水平 MCPyV 的 MCC 肿瘤相比，具有很少或没有可检测到的 MCPyV DNA 的 MCC 肿瘤具有高视网膜母细胞瘤癌基因表达，且预后较差。召开了一个共识小组，报告 MCC 和 MCPyV 病毒学、流行病学、分子病理学和临床管理的最新进展。在来自牙买加的 395 例 NHL 病例（按年龄、性别、历年和 HTLV 血清状态）与来自同一人群的 309 例对照相匹配，NHL 风险降低与白细胞介素 13 (IL13) Ex4+98A>G (rs20541) 比值比的多态性相关（ OR) AG/AA)=0.62, p=0.006, 血管细胞粘附分子 1 (VACM1) Ex9+ 14G>A 多态性 (rs1041163) OR [CT] 0.77，OR [CC] 0.35，趋势 p = 0.007。在仅限于成人 T 细胞白血病/淋巴瘤 (ATL) 患者和 HTLV 血清阳性对照患者的分析中，这种关联性更强，表明这些基因可能在 ATL 的发展中具有重要的病因学意义（使用美国 HIV/AIDS 癌症匹配研究，在 499,230 名患者中进行）艾滋病毒/艾滋病患者，肛门、子宫颈、口咽、阴茎、阴道和原位癌症和浸润性癌症的风险与一般人群相比，艾滋病患者的外阴感染率明显更高。在高效抗逆转录病毒治疗 (HAART) 时代（1996-2004），CD4 T 细胞计数低与浸润性肛门癌、浸润性宫颈癌以及原位阴道癌或外阴癌的风险增加相关。在男性中，1996-2004 年期间原位和浸润性肛门癌的发病率明显高于 1990-1995 年（原位癌增加 61%，浸润性癌症增加 104%）。随着时间的推移，其他癌症的发病率保持稳定。这些结果表明，艾滋病患者中与 HPV 相关的癌症风险增加，并且随着免疫抑制的增加而增加。 HAART 时代肛门癌发病率的增加表明，延长生存期可能与某些 HPV 相关癌症的风险增加有关。在一项关于艾滋病诊断后 4-27 个月内癌症风险的研究中，1996-2002 年 KS 发病率（335/100,000 人年）低于 1990-1995 年（1839/100,000 人年），NHL 发病率模式相似（即 390/100,000 人年） 1996-2002年和1990-1995年1066/10万人年）。 1996-2002年，每微升血液中CD4细胞计数每下降50个细胞，KS风险增加40%，中枢神经系统非霍奇金淋巴瘤亚型增加85%，弥漫性大B细胞淋巴瘤增加12%，但n伯基特淋巴瘤的增加是明显的。 1996-2002 年期间卡波西肉瘤（RR = 0.22，95% CI = 0.20 至 0.24）和非霍奇金淋巴瘤（RR = 0.40，95% CI = 0.36 至 0.44）的风险低于 1990-1995 年。在艾滋病毒/艾滋病患者 (PWHA) 中，1996 年至 2002 年艾滋病发病后 4 至 27 个月内患霍奇金淋巴瘤 (HL) 的风险明显高于之前。在具有 150 至 199 个 CD4 细胞/μL 的 PWA 中，发病率为每 10(5) py 53.7 例，而在 CD4 细胞少于 50 个/μL 的 PWA 中，发病率为每 10(5) py 20.7 例 (P(趋势) = .002 ）。对于每种 HL 亚型，发病率随着 CD4 计数的下降而下降，但结节性硬化比混合细胞性下降更急剧，从而增加了 PWA 中看到的混合细胞性 HL 的比例。在基于登记的艾滋病毒/艾滋病患者 (PWHA) 中，使用 3 种与艾滋病相关的癌症：KS、中枢神经系统非霍奇金淋巴瘤，对标准化发病率 (SIR) 的程度可能低估了癌症风险的相对风险 (RR) （中枢神经系统非霍奇金淋巴瘤）和宫颈癌。 SIR 大大低估了 KS 和 CNS NHL 的 RR，这可能是因为 PWHA 中 KS 和 CNS NHL 的相对风险异常高。我们测量了 360 名 HIV-1 感染者的血清中可溶性 CD23 (sCD23)、sCD27、sCD30、白细胞介素 (IL)-6、IL-10、总免疫球蛋白 E、C 反应蛋白和 Epstein-Barr 病毒 DNA 载量，并对候选基因中的 38 个单核苷酸多态性 (SNP) 进行了基因分型。我们使用主成分 (PC) 分析来总结血清标志物的个体间和纵向变化，并使用广义估计方程来模拟第一个 PC 和 38 个 SNP 之间的关系。 10 个 SNP 与血清水平的相关性具有统计学显着性，其中最强的是 IL13-1112C>T 与 sCD30、CC 趋化因子配体 5 (CCL5)-403G>A 与 sCD23 以及 CXC 趋化因子配体 12 (CXCL12)+535G>A 与 sCD23 相关。 IL-10（所有 p<0.01）。血清标志物第一 PC 的较高值与 CCL5-403A 相关，较低值与 IL13-1112T 相关。这些发现表明，总体上，Th2 标记物受到混合遗传影响，并且 HIV 感染者中循环 T 细胞的 Th2 极化与血清水平不一致。使用 KS 克隆性和基因表达研究的样本，我们发现横截面外周血中的 HHV8 负载与 KS 进展相关，并且在较小程度上与 KS 负担相关。其他相关因素包括低血红蛋白和低血小板。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。