Immunogenetics of Cervical and Vulvar Cancer

宫颈癌和外阴癌的免疫遗传学

• 批准号: 7015626
• 负责人: STEPHEN M SCHWARTZ
• 金额: $ 65.78万
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7015626
• 关键词: adenocarcinoma; alleles; cancer risk; carcinogenesis; cervix neoplasms; chemokine receptor; clinical research; gene environment interaction; gene expression; gene interaction; genetic markers; genotype; histocompatibility antigens; human papillomavirus; human tissue; immune response; immunogenetics; immunoregulation; polymerase chain reaction; single nucleotide polymorphism; squamous cell carcinoma; vulva neoplasms

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（由申请人提供）：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。基于大量人群的研究表明，肛门生殖器官癌之间存在强烈的家族关联。然而，导致HPV肛门生殖器癌变的具体遗传因素尚未得到全面研究。细胞介导的免疫机制，包括HLA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。在我们的计划项目拨款（CA 42792）中，我们目前被资助研究HLA I类等位基因与鳞状细胞宫颈癌风险之间的关系。本申请寻求资金，以扩大我们的hpv相关的肛门生殖癌症的免疫遗传学研究。具体而言，利用460例宫颈腺癌、426例宫颈鳞状细胞外阴癌和917例人群对照的现有DNA标本，我们将确定HLA I类和II类等位基因与宫颈腺癌和外阴癌风险之间的关系。我们将使用微卫星标记来确定与这些癌症和鳞状细胞宫颈癌（n=453）相关的HLA等位基因的扩展单倍型，以确定可能参与HPV肛门生殖器癌变的其他HLA区域位点。我们还将确定它们之间的关联