IMMUNOGENETICS OF HPV-RELATED CANCERS

HPV 相关癌症的免疫遗传学

基本信息

批准号：
7883490
负责人：
Stephen MARK Schwartz
金额：
$ 29.69万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
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/7883490
关键词：
Address Agonist Alleles Animals Anogenital cancer Anogenital venereal warts Antibody Formation Biological Assay Biology Cancer Etiology Candidate Disease Gene Case-Control Studies Cervical Cervical Adenocarcinoma Clinical Management Code DNA DNA Repair Data Dermal Development Disease Doctor of Philosophy ERCC1 gene ERCC3 gene Elements Engraftment Epidemiology Etiology Event Exposure to Funding Future Genes Genetic Genetic Polymorphism Genetic Variation Genomics Genotype Goals HLA Antigens Haplotypes Human Papillomavirus Human papilloma virus infection IL12A gene IL12B gene IL6 gene IRAK4 gene IRF3 gene Immune Immune response Immune system Immunogenetics Immunologics Immunosuppression Individual Infection Inherited Interferon Type II Interleukin-10 Interleukins Interview Knowledge Malignant Neoplasms Malignant neoplasm of cervix uteri Malignant neoplasm of vulva Mediating Methods Molecular Mutation Nucleotide Excision Repair Nucleotides Oncogene Proteins Organ Transplantation Pathogenesis Pattern Persons Play Population Population Control Principal Investigator Program Research Project Grants Proteins Receptor Signaling Recruitment Activity Research Resources Risk Role Signaling Molecule Single Nucleotide Polymorphism Skin Specimen Squamous Cell System TBK1 gene TLR3 gene TLR4 gene TLR7 gene TNF gene TOLLIP gene TRAF6 gene Testing Toll-Like Receptor 2 Toll-Like Receptor Pathway Toll-like receptors Transplant Recipients Tumor Antigens Tumor Suppressor Genes UV induced UV induced DNA damage Ultraviolet Rays Variant Viral Virus Virus Diseases Vulva Carcinoma Vulvar Squamous Cell Carcinoma Work cancer cell cancer risk cell growth clinically significant cytokine genital infection high risk neoplastic cell pathogen population based prevent programs receptor repair enzyme skin squamous cell carcinoma

项目摘要

Genital infection by genus alpha human papillomavirus (HPV) types is the necessary cause of cervical cancer and a large proportion of vulvar carcinomas. Accumulating evidence suggests that genus beta HPV types contribute to the development of squamous cell skin carcinoma (SCSC), particularly in organ transplant recipients (OTR). Although the molecular mechanisms through which HPV oncoproteins influence the development of anogenital and SCSC differ, an immunologic milieu that allows the virus and/or nascent tumor cells to escape host surveillance likely plays a key role in the etiology of these cancers. Our long-term goal is to clarify the role of immunogenetic factors in the etiology of HPV-related cancers. In the first specific aim, we will test the hypothesis that the risk of cervical and vulvar carcinoma is increased among persons carrying variant alleles of genes involved in the Toll-like receptor (TLR) pathway (TLR3, TLR4, TLR7, TLR9, TICAM1, T1CAM2, TIRAP, IRAKI, IRAK4, TOLLIP, TRAF6, TBK1, IKBKE, IRF3), a key component of the innate immune response. This aim will use resourcesDNA specimens and interview data from population- based cases of squamous cell cervical cancer (n=391), cervical adenocarcinomas (n=508), squamous cell vulvar carcinomas (n=535), and population controls (n=1,318)accumulated in the prior funding periods of the Program Project Grant. In the second specific aim, we will test the hypothesis that the risk of SCSC in OTR is increased among persons carrying variant alleles of genes involved in the immune response to HPV, tumor antigens, and/or UV light: human leukocyte antigen (HLA) (DRB1, DQB1, A, B, C, and G); TLR pathway (TLR4, TLR7, TICAM1, TICAM2, IRAKI, IRAK4, TOLLIP, TRAF6, TBK1, IKBKE, IRF3), immunomodulatory cytokines (IL10, IL12A, IL12B, IL6, IFNG and TNF), and nucleotide excision repair enzymes (XPB, XPC, XPD, XPF, XPG, and ERCC1). This aim will use DNA specimens and other data obtained from 250 SCSC cases and 250 controls recruited into Project 1. For the candidate genes other than the classical HLA-DRB1-DQB1, -A, -B, -C loci, we will capture the major patterns of genomic variation by choosing and assaying for tagging single nucleotide polymorphisms (tagSNPs). Analytic methods for multilocus genotype data will be used to estimate the associations with individual polymorphisms and inferred haplotypes. This project will provide new information about the role of inherited variation in immune response systems in the development of HPV-related cancers. LAY SUMMARY: Infection with cancer-causing human papillomaviruses (HPV) is common, but many infected persons do not develop cancer. This study will determine whether a person's genetic make-up influences whether HPV-related cancers occur, and could provide clues as to how such cancers might be prevented in the future.

人类乳头瘤病毒（HPV）类型的生殖器感染是宫颈的必要原因癌症和大部分外阴癌。积累的证据表明β属HPV属类型有助于鳞状细胞皮肤癌（SCSC）的发展，特别是在器官中移植受者（OTR）。尽管HPV癌蛋白会影响分子机制肛门生殖器和SCSC的发展不同，一种免疫环境，允许病毒和/或新生避免宿主监测的肿瘤细胞在这些癌症的病因中可能起关键作用。我们的长期目标是阐明免疫遗传因素在与HPV相关癌症的病因中的作用。在第一个特定目的，我们将检验以下假设：宫颈和外阴癌的风险增加携带类似受体（TLR）途径的基因的变体等位基因（TLR3，TLR4，TLR7，TLR9，TLR9， TICAM1，T1CAM2，TIRAP，IRAKI，IRAK4，TOLLIP，TRAF6，TBK1，IKBKE，IRF3），这是一个关键组成部分先天免疫反应。该目标将使用资源DNA标本和人群的访谈数据 - 基于鳞状细胞宫颈癌的病例（n = 391），宫颈腺癌（n = 508），鳞状细胞外阴癌（n = 535），人口控制（n = 1,318）在先前的资金期间积累计划项目赠款。在第二个特定目的中，我们将检验以下假设。携带与HPV免疫反应的基因的变异等位基因的人之间的OTR有所增加，肿瘤抗原和/或紫外线光：人类白细胞抗原（HLA）（DRB1，DQB1，A，B，C和G）； Tlr 途径（TLR4，TLR7，TICAM1，TICAM2，IRAKI，IRAK4，TOLLIP，TRAF6，TRAF6，TBK1，IKBKE，IRF3），IRF3），免疫调节细胞因子（IL10，IL12A，IL12B，IL6，IFNG和TNF）和核苷酸切除修复酶（XPB，XPC，XPD，XPF，XPG和ERCC1）。此目标将使用DNA标本和其他数据从250例SCSC案例和250个对照中获得的项目1。经典的HLA -DRB1 -DQB1，-a，-b，-c基因座，我们将通过捕获基因组变异的主要模式选择和分析用于标记单核苷酸多态性（TAGSNP）。分析方法多焦点基因型数据将用于估计与单个多态性和推断的单倍型。该项目将提供有关继承变异在免疫中的作用的新信息与HPV相关癌症开发的响应系统。摘要摘要：引起癌症的人乳头瘤病毒（HPV）的感染很常见，但许多感染者不发展癌症。这项研究将确定一个人的基因构成影响与HPV相关的癌症是否发生，并可以提供有关这种癌症如何的线索将来阻止。