Epidemiology and Natural History of Cancer-Associated Viruses

癌症相关病毒的流行病学和自然史

基本信息

批准号：
7733733
负责人：
SAM M MBULAITEYE
金额：
$ 583.39万
依托单位：
DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
依托单位国家：
美国
项目类别：
财政年份：
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/7733733
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Adrenal Cortex Hormones Adult Age Alleles Anemia Antibodies B-Lymphocytes BCL6 gene Biochemical Biological Assay Blood Blood Coagulation Factor Blood Platelets Breast Burkitt Lymphoma CD4 Lymphocyte Count CD4 Positive T Lymphocytes CUL5 gene CX3CL1 gene CXCL12 gene Calendar Case-Control Studies Categories Cells Cellularity Clinical Clonality Cohort Studies Collaborations Complex Conjunctival Squamous Cell Carcinoma Cyclophilin A Data Data Analyses Detection Development Diabetes Mellitus Diagnosis Disease Enrollment Epidemic Epidemiology Extramural Activities Family Fostering Gender Gene Expression Genes Genotype Goals HIV HIV-1 HLA Class I Genes HTLV-1 Infection Haplotypes Head and Neck Cancer Hemoglobin Hemophilia A Hepatitis B Virus Hepatitis C Hepatitis C virus Hispanics Hodgkin Disease Homosexuals Human Human Herpesvirus 8 Human T-lymphotropic virus 1 Hypersensitivity IL18 gene IL4 gene IL4R gene Immunity Immunologic Deficiency Syndromes Immunosuppression Incidence Individual Infection Infectious Agent Inflammation Interleukin-10 Interleukin-13 Interleukin-4 Island Jamaica Kaposi Sarcoma Laboratories Lactate Dehydrogenase Lactate Dehydrogenases Lesion Liver Lymphocyte Lymphoma Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of lung Malignant neoplasm of penis Malignant neoplasm of testis Methods Multicenter Hemophilia Cohort Study Natural History Neuraxis Neurodegenerative Disorders Nicotine Non-Hodgkin&apos s Lymphoma Normal Cell Organ Transplantation Participant Pattern Persons Population Procedures Proviruses RANTES Radiation Randomized Clinical Trials Rate Registries Relative (related person)Relative Risks Research Risk Role Sampling Satellite Viruses Sclerosis Sicily Single Nucleotide Polymorphism Smoke Spinal Cord Diseases T-Lymphocyte TSG101 gene Testing Therapeutic immunosuppression Time Variant Viola Viral Load result Virus Week Woman Y Chromosome base cancer risk case control cohort eosinophil follow-up human CX3CR1 protein human leukocyte antigen gene large cell Diffuse non-Hodgkin&apos s lymphoma leukemia/lymphoma malignant breast neoplasm malignant stomach neoplasm men multidisciplinary neoplastic cell peripheral blood prospective transmission process trend

项目摘要

This project is a comprehensive, multidisciplinary effort to understand the natural history and modes of transmission of viruses and other infectious agents that are associated with cancer. With numerous intramural and extramural laboratory, clinical, and epidemiologic collaborators, and a core of prospective cohort and case-control studies, the effort is focused on human immunodeficiency virus (HIV), human T-lymphotropic virus types I and II (HTLV-I/-II), hepatitis C virus (HCV), and Kaposi sarcoma-associated herpesvirus (KSHV, also called human herpesvirus 8 or HHV-8). 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/AIDS was shown to be associated with variants in several immunity-related genes (HLA/KIR, cyclophilin A, RANTES, CX3CR1), and likelihood of hepatitis B virus (HBV) clearance was associated with variants in IL10 and IL20. Among HIV-uninfected participants, spontaneous clearance of HCV was found to be associated with infection at a very young age and in relatively recent calendar years. In collaboration, AIDS progression rate was related to differences in several genes related to immunity. The hepatitis C virus (HCV) epidemic in the U.S. hemophilia population was reconstructed, revealing that most infections occurred prior to use of clotting factor concentrates. Spontaneous clearance of HCV infection was shown to be greatly increased with hepatitis B virus (HBV) co-infection. In addition, among hemophiliacs without HIV, HCV clearance also was clustered in families and increased with early age at infection. An HBV viral load assay was developed, and clearance of HBV was related to variants in the IL-18 gene. Progression of HIV/AIDS was shown to be associated with variants in several immunity-related genes (CUL5, cyclophilin A, TSG101, and HLA/KIR), and new methods were developed to analyze these complex relationships. A four-year case-control study of classical (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. KS transdermal nicotine trial " A 15-week randomized clinical trial was completed, showing that use of transdermal patches to directly deliver nicotine to classic KS lesions was neither harmful nor beneficial. Among HTLV-I-infected people in Jamaica, common variants in HLA Class I genes were associated with a significantly increased risk of adult T-cell leukemia/lymphoma (ATL) and with non-significantly increased levels of HTLV-I proviral load. Common HLA variants were not related to HTLV-associated myelopathy. In a study comparing HTLV-1 carriers with HTLV-1 negative subjects, markers of HTLV-1 infection (infection status, antibody titer, and provirus load) were associated with hematologic and biochemical alterations, such as lymphocyte abnormalities, anemia, decreased eosinophils, and elevated lactate dehydrogenase levels. Using the the U.S. HIV/AIDS Cancer Match Study, study of human immunodeficiency virus (HIV)-infected persons with modest immunosuppression, before the onset of acquired immunodeficiency syndrome (AIDS), demonstrated elevated risk for Kaposi sarcoma (KS, SIR 1,300), non-Hodgkin lymphoma (NHL, 7.3), cervical cancer (2.9) and several non-AIDS-defining malignancies, including Hodgkin lymphoma (5.6 ) and cancers of the lung (2.6 ) and liver (2.7). Non-AIDS-defining cancers comprised 31.4% of cancers in 1991-1995, versus 58.0% in 1996-2002. 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. The risk for squamous cell carcinoma of the conjunctiva (SCCC) was observed to be increased in persons with AIDS (SIR, 12.5; 95% CI 7.0 - 20.6) using data from the US HIV/AIDS cancer match study. The relative proportion of was higher among Hispanics and among individuals residing in regions with high ambient ultra violet (u.v.) radiation supporting a role for immunosuppression in SCCC genesis. Risk was unrelated to gender, HIV exposure category, CD4 lymphocyte count, and time relative to AIDS-onset. For HIV/AIDS lymphomas, an analysis of 179 incident lymphomas and matched controls among HIV-1-seropositive homosexual men in the Multicenter AIDS Cohort Study (MACS). Subjects were genotyped for single nucleotide polymorphisms (SNPs) in B-cell stimulatory (IL10, IL10RA, CXCL12, CCL5), allergy-related (IL13, IL4, IL4R) and inflammation-related (BCL6) genes. Compared to the "high IL10" genotype -592CC, carriers of the IL10-592A allele were at lower risk of NHL, and the putative "low-producer IL10" haplotype, -1082A/-819T/-592A was less frequent in cases than controls (16% vs 22%, P=0.03). None of other studied genes differed significantly between cases and controls. Using samples from the KS clonality and gene expression study, we tested the hypothesis that whole KS cells can be transmitted sexually was examined in 25 women by looking for presence of Y-chromosome in KS tumor cells as compared to normal cells. None were positive. Data on human herpesvirus 8 load in peripheral blood has been analyzed and shown to be 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.

该项目是一项全面的，多学科的努力，旨在了解病毒和其他与癌症相关的传播剂的自然历史和传播方式。 With numerous intramural and extramural laboratory, clinical, and epidemiologic collaborators, and a core of prospective cohort and case-control studies, the effort is focused on human immunodeficiency virus (HIV), human T-lymphotropic virus types I and II (HTLV-I/-II), hepatitis C virus (HCV), and Kaposi sarcoma-associated疱疹病毒（KSHV，也称为人类疱疹病毒8或HHV-8）。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/AIDS的进展与多种免疫相关基因（HLA/KIR，环磷脂A，Rantes，CX3CR1）的变异相关，并且乙型肝炎病毒（HBV）清除率与IL10和IL20中的变体有关。在艾滋病毒未感染的参与者中，发现HCV的自发清除与很小的年龄和相对较新的日历年的感染有关。在协作中，艾滋病进展率与与免疫相关的几个基因的差异有关。美国血友病人群中的丙型肝炎病毒（HCV）流行已重建，表明大多数感染发生在使用凝结因子浓缩物之前。肝炎病毒（HBV）共感染显示，HCV感染的自发清除率大大增加。此外，在没有HIV的血友病中，HCV清除率也聚集在家庭中，并随着感染时的幼年而增加。开发了HBV病毒载荷测定法，HBV的清除与IL-18基因中的变体有关。 HIV/AIDS的进展与几个免疫相关基因（CUL5，环磷脂A，TSG101和HLA/KIR）的变异有关，并开发了新方法来分析这些复杂关系。整个西西里岛（CKS和KSHV是特有的），对古典（非AID）Kaposi肉瘤和KSHV感染进行了四年的病例对照研究。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。 KS透皮尼古丁试验“完成了15周的随机临床试验，表明使用透皮斑块直接将尼古丁传递到经典的KS病变既不有害也不是有益的。在HTLV-i感染的牙买加人中，HLA类I类基因中的常见变异与不合适的风险相关，与成年likemia and-lymia and-lymia clific and-lymia callimia climia aftifialia ly-sigramia ly-likia ly-likemia ly-likemaiy ly-ly-ly-ly-ly-likia ly-likemairantial liukemaiy ly-likemaiy（ HTLV-I前毒性载荷与HTLV相关的脊髓病无关贫血，嗜酸性粒细胞降低，乳酸脱氢酶水平升高，使用美国艾滋病毒/艾滋病癌症匹配的研究，人类免疫缺陷病毒（HIV）感染的人具有适度的免疫抑制作用，在获得的免疫缺陷型症状（艾滋病）的风险中，sir sir sir sir sir sir sir sir sir sir kaposi，kaposa aa aa a a a a a a a a a a a a a a a a a a a a a a a估计（kaposa）（kaposa），kapgosibaive the。淋巴瘤（NHL，7.3），宫颈癌（2.9）和几种定义的恶性肿瘤，包括霍奇金淋巴瘤（5.6）和肺癌（2.6）和肝脏（2.7）。 1995年至1995年的非辅助癌症占癌症的31.4％，在1996 - 2002年为58.0％。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。使用来自美国HIV/AIDS癌症匹配研究的数据，观察到与艾滋病患者（SIR，12.5; 95％CI 7.0-20.6）的结膜（SCCC）鳞状细胞癌的风险增加。西班牙裔和居住在具有高环境超紫色（U.V.）辐射的地区的个体中，相对比例较高，这支持了SCCC创世记中免疫抑制作用的作用。风险与性别，HIV暴露类别，CD4淋巴细胞计数以及相对于艾滋病发作的时间无关。对于HIV/AIDS淋巴瘤，在多中心艾滋病队列研究（MACS）中，对HIV-1阳性同性恋男性的179例淋巴瘤和对照组进行了分析。对B细胞刺激（IL10，IL10RA，CXCL12，CCL5）中的单核苷酸多态性（SNP）进行基因分型，与过敏相关（IL13，IL4，IL4R）和炎症相关（BCL6）基因（BCL6）基因。与“高IL10”基因型-592CC相比，IL10-592A等位基因的载体的风险较低，推定的“低生产者IL10”单倍型，-1082A/-819T/-592A在案例中的频率低于对照组（16％vs 22％，p 22％，p = 0.03）。病例和对照组之间的其他研究基因没有显着差异。使用来自KS克隆性和基因表达研究的样品，我们通过寻找与正常细胞相比在KS肿瘤细胞中寻找Y染色体的Y-染色体，从而在25位女性中检查了整个KS细胞的假设。没有一个是积极的。已经分析了有关外周血中人类疱疹病毒8负载的数据，并证明与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。

项目成果

期刊论文数量（20）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Absence of Y-chromosome sequences in tumors from African women with AIDS-related Kaposi sarcoma.

患有艾滋病相关卡波西肉瘤的非洲女性肿瘤中缺乏 Y 染色体序列。

DOI：
10.1016/j.canlet.2006.07.008
发表时间：
2007
期刊：
Cancer letters
影响因子：
9.7
作者：
Mbulaiteye,SamM;Sternberg,LawrenceR;Nsubuga,MartinM;Anver,MiriamR;Mehta,Meghna;Biryahwaho,Benon;Kambugu,Fred;Rabkin,CharlesS;Biggar,RobertJ
通讯作者：
Biggar,RobertJ

Immunological detection of viral large T antigen identifies a subset of Merkel cell carcinoma tumors with higher viral abundance and better clinical outcome.

DOI：
10.1002/ijc.25136
发表时间：
2010-09-01
期刊：
INTERNATIONAL JOURNAL OF CANCER
影响因子：
6.4
作者：
Bhatia, Kishor;Goedert, James J.;Modali, Rama;Preiss, Liliana;Ayers, Leona W.
通讯作者：
Ayers, Leona W.

IL1B polymorphisms and gastric cancer risk.

IL1B 多态性与胃癌风险。

DOI：
10.1158/1055-9965.epi-06-0925
发表时间：
2007
期刊：
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
影响因子：
0
作者：
Camargo,MConstanza;Mera,Robertino;Correa,Pelayo;PeekJr,RichardM;Piazuelo,MBlanca;Sicinschi,Liviu;Schneider,BarbaraG;Zabaleta,Jovanny;Fontham,ElizabethTH;Goodman,KarenJ;Ryckman,KelliK
通讯作者：
Ryckman,KelliK

A case-control study of cancer of the uterine cervix in Uganda.

乌干达宫颈癌的病例对照研究。

DOI：
10.1097/01.cej.0000243863.22137.b7
发表时间：
2007
期刊：
European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP)
影响因子：
0
作者：
Newton,Robert;Ziegler,John;Casabonne,Delphine;Beral,Valerie;Mbidde,Edward;Carpenter,Lucy;MaxwellParkin,D;Wabinga,Henry;Mbulaiteye,Sam;Jaffe,Harold;UgandaKaposi'sSarcomaStudyGroup
通讯作者：
UgandaKaposi'sSarcomaStudyGroup

Infection with human herpes virus type 8 in an area at high prevalence for hepatitis C virus infection in southern Italy.

意大利南部丙型肝炎病毒感染高发地区发生 8 型人类疱疹病毒感染。