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。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）（如果可用）可用来测量传染剂的负荷，包括HIV，HTLV-I/-II，HCV和KSHV，也称为HHV8，也称为HHV8，病毒药物或宿主的遗传变异，以表征生物标志物与癌症的生物标志物相关。第二项多中心血友病队列研究（MHCS-II）招募并完成了2500多名HCV暴露于血友病的人的前瞻性随访。建立了一个公共网站（HTTPS：MHCS-II.RTI.org），并具有背景信息和数据分析程序。 HIV向AIDS的进展与线粒体和Y染色体DNA单倍体以及APOBEC3B和IL10基因中的变体有关。丙型肝炎病毒（HBV）清除的可能性与IL10和IL20中的变体有关，丙型肝炎病毒（HCV）清除的可能性与IL18和免疫球蛋白GM等位基因中的变体有关。整个西西里岛的经典（非AID）Kaposi肉瘤和KSHV感染的四年病例对照研究完成（CKS和KSHV是地方性的）。当前吸烟随着糖尿病和使用皮质类固醇的使用而显着且独立增加，经典的KS风险大大降低了。经典KS也随着与火山相关的土壤而增加的住宅暴露铬luvisols也增加了。艾滋病毒/艾滋病患者的默克尔细胞癌（MCC）的风险显着增加，这是一种高致命的神经内分泌皮肤癌，其中其他人最近发现了一种新型的多瘤病毒（MCPYV）。与MCPYV较高的MCC肿瘤相比，发现几乎没有可检测到的MCPYV DNA的MCC肿瘤对视网膜母细胞瘤癌基因的表达很高，预后较差。召集了一个共识组，报告了MCC和MCPYV病毒学，流行病学，分子病理学和临床管理的最先进。在牙买加的395例NHL案件中，按年龄，性别，日历年和HTLV Cerostatus与同一人群的309个对照相匹配，NHL风险降低与Interleukin 13（IL13）EX4+98a+98a> g（rs20541）的多态性有关（VACM1）EX9+ 14G>多态性（RS1041163）或[CT] 0.77或[CC] 0.35，P的趋势= 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,与普通人群相比，艾滋病患者的口咽，阴茎，阴道和外阴明显更高。在高度活跃的抗逆转录病毒疗法（HAART）时代（1996-2004）中，CD4 T细胞数量低与侵袭性肛门癌，侵袭性宫颈癌以及原位阴道或外阴癌的风险增加有关。在男性中，1996 - 2004年期间原位和侵入性肛门癌的发病率显着高于1990 - 1995年（原位癌症增加了61％，入侵癌症增加了104％）。随着时间的流逝，其他癌症的发病率是稳定的。这些结果表明，患有艾滋病患者的HPV相关癌症风险增加，并随着免疫抑制的增加而增加。 HAART时代的肛门癌发病率增加表明，长期生存可能与某些HPV相关癌症的风险增加有关。在一项在AIDS诊断后的4-27个月期间对癌症风险的研究中，KS的发病率在1996-2002（335/100,000人年）低于1990- 1995年（1839/100,000人年），NHL的发生率模式相似，即390/100,000人年（1996-2002和1066/1066/100,000）的人数相似。在1996年至2002年，对于每微层血液的CD4细胞计数下降的每次下降，KS风险增加了40％，中枢神经系统非霍奇金淋巴瘤亚型的亚型增加了85％，弥漫性大B细胞淋巴瘤为12％，但N升高是Burkitt Lymphoma的。 Kaposi Sarcoma（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）在1996 - 2002年期间的风险低于1990 - 1995年。在患有艾滋病毒/艾滋病（PWHAS）的人中，艾滋病发作后4至27个月的霍奇金淋巴瘤（HL）的风险显着高于早期。 150至199 CD4细胞/MUL的PWAS的发病率为每10（5）PY，而在PWA中，PWAS的发病率少于50个CD4细胞/mul，每10（5）PY'S（P（趋势）= .002）。对于每种HL亚型，随着CD4计数的下降，发生率降低，但结节性硬化比混合细胞性降低了，从而增加了PWA中混合细胞HL的比例。使用3种与AIDS相关的癌症研究了基于注册表中的艾滋病毒/艾滋病患者（PWHA）的癌症风险相对风险（RR）的范围：KS，中枢神经系统非霍奇金淋巴瘤（CNS NHL）和宫颈癌。 SIRS显然低估了KS和CNS NHL的RR，这可能是由于PWHA中KS和CNS NHL的相对风险极高的。我们测量了360个HIV-1感染的CD23（SCD23），SCD27，SCD30，介体（IL）-6，IL-10，总免疫球蛋白E，C-反应蛋白，C-反应蛋白和Epstein-Barr病毒DNA载荷和基因型单核核酸酯（Snplist in Clotis）的血清水平。我们使用主成分（PC）分析来总结血清标记中的个体间和纵向变化，并概括了估计方程，以模拟第一PC与38个SNP之间的关系。十个SNP与血清水平的关联具有统计学意义，其中最强的是IL13-1112C> t，与SCD30，CC趋化因子配体5（CCL5）-403G> A具有SCD23和CXC趋化因子配体12（CXCL12）+535G> a，与IL-100（All P <0.01）。血清标记的较高值与CCL5-403A相关，较低的值与IL13-1112T有关。这些发现表明，对Th2标记的总体影响以及HIV感染受试者中循环T细胞和血清水平的Th2极化的混合遗传影响。使用来自KS克隆性和基因表达研究的样品，我们表明横截面外周血中的HHV8载荷与KS进展有关，并且在较小程度上与KS负担有关。其他相关性包括低血红蛋白和低血小板。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。