Immunogenetics of Cervical and Vulvar Cancer

宫颈癌和外阴癌的免疫遗传学

• 批准号: 7195107
• 负责人: STEPHEN M SCHWARTZ
• 金额: $ 63.78万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195107
• 关键词: Alleles; Anogenital cancer; Antigen Presentation; Antigen Presentation Pathway; Biology; CXCL12 gene; Cells; Cervical; Cervical Adenocarcinoma; Cervix Uteri; Characteristics; Chemokine Receptor Gene; Class; Cytokine Gene; Cytokine Receptors; DNA; Development; Disease; Epidemiology; Equilibrium; Funding; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genotype; HLA Antigens; Haplotypes; Human; Human Papilloma Virus Vaccine; Human Papillomavirus; Human papilloma virus infection; IL4 gene; IL5 gene; IL8 gene; Immune; Immune Response Genes; Immune response; Immunogenetics; Immunologic Surveillance; Inherited; Interleukin-12; Interleukin-4; Interleukin-5; Interleukins; Investigation; Ligands; Link; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of cervix uteri; Malignant neoplasm of vulva; Mediating; Microsatellite Repeats; Mutation; Neoplasms; Numbers; Oncogenic; Papillomavirus; Pathway interactions; Population; Population Control; Program Research Project Grants; Receptor Gene; Research; Research Personnel; Risk; Risk Factors; Single Nucleotide Polymorphism; Specimen; Squamous Cell; TNF gene; Testing; Tumor Antigens; Vaccines; Vulva; Vulva Carcinoma; Vulvar Squamous Cell Carcinoma; base; cancer risk; carcinogenesis; chemokine; cigarette smoking; clinically significant; cytokine; gene environment interaction; gene interaction; genetic association; genetic risk factor; interest; leukocyte antigen typing; programs; receptor; response; tumor; tumor progression

DESCRIPTION (provided by applicant): Human papilloma virus (HPV) infection is the necessary cause of all cervical neoplasia and the majority of vulvar cancer. Large population-based studies show strong familial associations among anogenital cancers. However, the specific genetic factors that contribute to HPV anogenital carcinogenesis have not been comprehensively studied. Cell-mediated immune mechanisms, including HLA and type 1 and type 2 cytokines, are crucial determinants of the host response to HPV infection. In our Program Project Grant (CA 42792), we are currently funded to examine the association between HLA class I alleles and squamous cell cervical cancer risk. This application seeks funding to expand our investigation of the immunogenetics of HPV-related anogenital cancers. Specifically, using existing DNA specimens on 460 cervical adenocarcinomas, 426 squamous cell vulvar carcinomas, and 917 population controls, we will determine associations between HLA class I and class II alleles and risks of cervical adenocarcinoma and vulvar carcinoma. We will use microsatellite markers to determine extended haplotypes of HLA alleles associated with these cancers, and with squamous cell cervical cancer (n=453), to identify additional HLA-region loci potentially involved in HPV anogenital carcinogenesis. We also will determine associations between these anogenital cancers and multiple single nucleotide polymorphisms and haplotypes in 17 cytokine genes (primarily interleukins), and their receptors or receptor antagonists (40 genes in total), known or suspected of being involved in type 1 and 2 responses or anogenital carcinogenesis. Finally, we will test the hypothesis that squamous cell cervical cancer, cervical adenocarcinoma, and squamous vulvar carcinoma are associated with common genetic variation in the chemokine receptor gene CXCR4 (mutations in which are linked to inherited impaired immune response to HPV) and its ligand, SDF1. Secondary aims include exploration of gene-gene interactions (e.g., among ligand-receptor gene pairs and genes involved in common adaptive immune response pathways) and gene-environment interactions (cigarette smoking and cytokine or cytokine receptor genotypes). This study will be the most comprehensive assessment of anogenital cancer immunogenetics to date, and will provide new information on inherited predisposition to these cancers, with potential implications for the development and/or implementation of HPV vaccines.

描述(申请人提供)：人乳头瘤病毒(HPV)感染是所有宫颈肿瘤和大多数外阴癌的必要原因。大量基于人群的研究表明，肛门癌之间存在很强的家族相关性。然而，导致HPV肛门生殖道癌变的具体遗传因素尚未得到全面研究。细胞免疫机制，包括人类白细胞抗原和1型和2型细胞因子，是宿主对HPV感染反应的关键决定因素。在我们的计划项目赠款(CA 42792)中，我们目前被资助研究人类白细胞抗原I类等位基因与宫颈鳞癌风险之间的关联。这项申请寻求资金，以扩大我们对HPV相关肛门生殖道癌的免疫遗传学的研究。具体地说，利用460例宫颈腺癌、426例外阴鳞状细胞癌和917例人群对照的现有DNA样本，我们将确定人类白细胞抗原I类和II类等位基因与宫颈癌和外阴癌的风险之间的关联。我们将使用微卫星标记来确定与这些癌症和宫颈鳞状细胞癌(n=453)相关的HLA等位基因的扩展单倍型，以确定其他可能与HPV肛门生殖道癌相关的HLA区域基因座。我们还将确定它们之间的关联 肛门生殖器癌和17个细胞因子基因(主要是白介素类)及其受体或受体拮抗剂(总共40个基因)的多个单核苷酸多态和单倍型，已知或怀疑参与类型1和2的反应或肛门生殖道癌的发生。最后，我们将检验这一假设，即宫颈鳞状细胞癌、子宫腺癌和外阴鳞癌与趋化因子受体基因CXCR4及其配体SDF1的常见基因变异有关(CXCR4基因突变与对HPV的遗传免疫反应受损有关)。次要目标包括探索基因-基因相互作用(例如，配体-受体基因对和参与常见适应性免疫反应途径的基因之间的相互作用)和基因-环境相互作用(吸烟和细胞因子或细胞因子受体基因类型)。这项研究将是迄今为止对肛门生殖道癌免疫遗传学最全面的评估，并将提供关于这些癌症遗传易感性的新信息，对HPV疫苗的开发和/或实施具有潜在的意义。