Immunogenetics of Cervical and Vulvar Cancer

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。大量基于人群的研究表明肛门生殖器癌之间存在强烈的家族关联。然而，导致HPV肛门生殖器癌发生的特定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。在我们的计划项目补助金（CA 42792），我们目前的资助，以检查HLA I类等位基因和鳞状细胞宫颈癌风险之间的关联。该申请寻求资金，以扩大我们对HPV相关肛门生殖器癌免疫遗传学的研究。具体而言，使用现有的DNA标本460宫颈腺癌，426外阴鳞状细胞癌，和917人口对照，我们将确定HLA I类和II类等位基因和宫颈腺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相关的HLA等位基因的扩展单倍型，并与鳞状细胞宫颈癌（n=453），以确定其他可能参与HPV肛门生殖器癌变的HLA区域基因座。我们还将确定这些之间的关联 肛门生殖器癌和17个细胞因子基因（主要是白细胞介素）及其受体或受体拮抗剂（共40个基因）的多个单核苷酸多态性和单倍型，已知或怀疑参与1型和2型反应或肛门生殖器癌发生。最后，我们将检验以下假设：宫颈鳞状细胞癌、宫颈腺癌和外阴鳞状细胞癌与趋化因子受体基因CXCR 4（其中突变与对HPV的遗传性免疫应答受损有关）及其配体SDF 1的常见遗传变异相关。次要目的包括探索基因-基因相互作用（例如，在配体-受体基因对和参与常见适应性免疫应答途径的基因之间）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型）。这项研究将是迄今为止对肛门生殖器癌免疫遗传学的最全面评估，并将提供有关这些癌症遗传易感性的新信息，对HPV疫苗的开发和/或实施具有潜在影响。

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.