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。 在美国涵盖了15年（1991-2005）的艾滋病和非辅助癌症的风险分析。美国艾滋病人口从1991年的96,179人扩大了四倍，增至2005年的413,080。这些增加主要是由于40岁或40岁以上的人。大约有79个656癌发生在艾滋病人群中。定义癌症的数量从1991年的34,587人减少了三倍以上，增加到2005年的10,325次癌症。 ptrend .001）。相反，在同一时间里，定义癌症的数量增加了大约三倍（3193至10,059癌； ptrend .001）。肛门（206至1564次癌症），肝脏（116至583次癌症），前列腺（87至759次癌症）和肺癌（875至1882年的癌症）和Hodgkin Lymphoma（426至897 Cancers）的癌症数量。在美国34个州的仅艾滋病毒人口中，估计有2191个非辅助癌症发生在2004 - 2007年期间，其中包括454个肺，166个乳房和154个肛门癌。 这种日益增长的负担需要针对美国艾滋病毒/艾滋病癌症匹配的针对性的预防癌症和治疗策略，在567名，865名艾滋病毒/艾滋病患者中，BL的发生率显示出儿科和成人/老年年龄在儿科和成人/老年年份中有两个特异性发病率，并且随着CD4淋巴细胞计数的降低。与非BL NHL相比，BL的双峰峰表明，不同年龄的非肿瘤风险因素的影响。对1980 - 2007年期间有AIDS的人的AIDS定义恶性肿瘤的比例进行了分析。 在83,252 ks病例中，约有82％，351,618例DLBCL病例中的6.0％，伯基特淋巴瘤病例中有20％，27,265个CNS淋巴瘤病例中的27％，在1980年2007年期间，在AIDS中发生了375,452例宫颈癌中的0.42％。 1990年代初（1990-1995：KS为90％，DLBCL为10％，伯基特淋巴瘤为48％，CNS淋巴瘤的KS和AIDS定义NHL的比例在1990年代初达到峰值，ks的比例为90％，KS淋巴瘤的比例为48％，随后降低了70％，ks占DLB的5％，占BLBCL的比例为5％，CN占21％的cn，CN的比例为13％，CN的比例为13％。随着时间的推移，患有艾滋病的人的癌症从1980 - 1991年的0.11％增加到2001 - 2007年的0.71％，而艾滋病的男性则降低了50％。来自法国的64例HIV患者的淋巴瘤病例与抗逆转录病毒疗法（CART）起始的时间间隔有关。 50-99 CD4细胞/mm。卡车开始后霍奇金淋巴瘤的风险很快就显着增加，这在很大程度上是由CD4计数来解释的。使用263 254名成年人和AIDS的青少年（1980-2004）的数据，美国HACM，我们表明，2个主要的艾滋病癌症的风险升高了：kaposi sarcoma：kaposi sarcoma：sirs，5321和1347和1347 and Sirsivily and Sirsivily and Sirsively and Sypively and Sypively and Sypsively and Sypsively ins Spirivise ins Siss Spirively ins Siss Spirively ins Siss Spirivise and Syp Siss Sist Sived）。 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来自乌干达，加纳和坦桑尼亚的非洲伯基特淋巴瘤病例，年龄特异性的疟疾生物标志物（患病率，负载和基因型的数量）与恶性疟原虫疟原虫疟原虫的混合基因型的数量相关，但与帕拉斯群岛的患病或负载无关。一项研究，以评估伯基特淋巴瘤的临床和局部病理诊断的准确性，通过外部病理审查诊断评估，并了解乌干达1医院的资源受限环境中组织病理学实践的局限性。局部病理实验室程序不一致且次优，尤其是针对组织固定。在88例临床假定的BL病例中，有63例被审查，仅确认了75％。在病理学局部诊断的患者中，确认了82％。 通过纳入具有相似临床表现的其他疾病，可以降低BL临床诊断的准确性。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SE36抗原的新型抗体测量疟疾免疫力。 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.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的住宅暴露而增加。Merkel细胞多瘤病毒（MCPYV）最近在默克尔细胞癌（MCC）中发现，这是一种临床和病理上异质性神经内分泌细胞的临床和病理异质性恶性肿瘤。我们开发了组织微阵列（TMA），以表征候选肿瘤细胞蛋白的免疫组织化学染色和定量PCR分析，以检测MCPYV并测量病毒载量。在23个（74％）的原发性MCC肿瘤中有19个（74％）中检测到MCPYV，但其中8个每300个细胞的病毒拷贝少于1个病毒拷贝。病毒丰度为0.06-1.2病毒拷贝/细胞直接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 OR = 0.003）。较高的病毒丰度肿瘤往往与p53表达较低，诊断年龄较小和生存期更长（p or = 0.08）有关。使用多中心艾滋病队列研究（MAC）的数据，我们表明，至少一份c soperrairage copriage carriage copers of copies copies copies copers copies copers copers copies copers copers contery contery contery copers的较低率（相比之下）与降低的艾滋病相关（相比之下） （CC与CT/TT：OR = 0.3; 95％CI 0.1，0.7），但不是系统地（CC与CT/TT：OR = 1.0; 95％CI 0.5，1.9）（pheterogenity = 0.03）。运输“低IL10”单倍型RS1800896_A/RS1800871_T/RS1800872_A的两份副本与淋巴瘤风险降低相关，这会随副本数量而变化（Ptrend = 0.02）。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。