IMMUNOGENETICS OF HPV-RELATED CANCERS

HPV 相关癌症的免疫遗传学

• 批准号: 7300322
• 负责人: Stephen MARK Schwartz
• 金额: $ 27.18万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7300322
• 关键词: Address; Agonist; Alleles; Animals; Anogenital cancer; Anogenital venereal warts; Antibody Formation; Biological Assay; Cancer Etiology; Candidate Disease Gene; Case-Control Studies; Cervical; Cervical Adenocarcinoma; Class; Clinical Management; Code; DNA; DNA Repair; Data; Dermal; Development; Disease; Doctor of Philosophy; ERCC1 gene; ERCC2 gene; ERCC3 gene; ERCC5 gene; Elements; Engraftment; Etiology; Event; Exposure to; Funding; Future; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genomics; Genotype; Goals; HLA Antigens; Haplotypes; Human; Human Development; 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; Light; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of vulva; Mediating; Medical Surveillance; Methods; Molecular; Mutation; Nucleotide Excision Repair; Nucleotides; Oncogene Proteins; Organ Transplantation; Papillomavirus; 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; TNF receptor-associated factor 6; TOLLIP gene; TRAF6 gene; Testing; Therapeutic immunosuppression; Toll-Like Receptor 2; Toll-Like Receptor Pathway; Toll-like receptors; Transplant Recipients; Tumor Antigens; Tumor Suppressor Genes; UV induced; UV induced DNA damage; Variant; Viral; Virus; Virus Diseases; Vulva Carcinoma; Vulvar Squamous Cell Carcinoma; Work; base; cancer cell; cancer risk; case-based; cell growth; cytokine; genital infection; human IRAK4 protein; human TOLLIP protein; neoplastic cell; pathogen; prevent; programs; receptor; repair enzyme; skin squamous cell carcinoma

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.

人乳头瘤病毒（HPV）感染是导致宫颈癌的主要原因。 癌症和大部分外阴癌。越来越多的证据表明， 类型有助于鳞状细胞皮肤癌（SCSC）的发展，特别是在器官 移植受体（OTR）。虽然HPV癌蛋白影响的分子机制 肛门生殖器和SCSC的发育不同，免疫环境允许病毒和/或新生 肿瘤细胞逃避宿主监视可能在这些癌症的病因学中起关键作用。我们的长期 目的是阐明免疫遗传因素在HPV相关癌症病因学中的作用。在第一个具体的 目的：我们将检验宫颈癌和外阴癌风险在人群中增加的假设。 携带参与Toll样受体（TLR）途径的基因的变体等位基因（TLR 3，TLR 4，TLR 7，TLR 9， TICAM 1、T1CAM 2、TIRAP、IRAKI、IRAK 4、TOLLIP、TRAF 6、TBK 1、IKBKE、IRF 3）， 先天免疫反应这一目标将利用资源从人群中提取的DNA样本和访谈数据- 宫颈鳞状细胞癌（n=391）、宫颈腺癌（n=508）、宫颈鳞状细胞癌（n=508） 外阴癌（n=535）和人群对照（n= 1，318）以往供资期间累积的 计划项目补助金。在第二个具体目标中，我们将检验以下假设： 在携带参与对HPV的免疫应答的基因的变异等位基因的人中， 肿瘤抗原和/或UV光：人白细胞抗原（HLA）（DRB 1、DQB 1、A、B、C和G）; TLR 途径（TLR4、TLR7、TICAM 1、TICAM 2、IRAKI、IRAK 4、TOLLIP、TRAF 6、TBK 1、IKBKE、IRF 3）， 免疫调节细胞因子（IL 10、IL 12 A、IL 12 B、IL 6、IFNG和TNF）和核苷酸切除修复 酶（XPB、XPC、XPD、XPF、XPG和ERCC 1）。这一目标将使用DNA标本和其他数据 从项目1招募的250例SCSC病例和250例对照中获得。对于候选基因， 经典的HLA-DRB 1-DQB 1，-A，-B，-C基因座，我们将通过以下方式捕获基因组变异的主要模式： 选择和测定标记单核苷酸多态性（tagSNPs）。分析方法 多位点基因型数据将用于估计与个体多态性的关联， 推断的单倍型。该项目将提供有关遗传变异在免疫系统中作用的新信息。 反应系统在HPV相关癌症发展中的作用。 摘要：感染致癌的人乳头瘤病毒（HPV）是常见的，但许多 受感染的人不会患上癌症。这项研究将确定一个人的基因组成 影响是否发生HPV相关的癌症，并可能提供有关这些癌症如何发生的线索。 防止在未来。