Genetic Susceptibility to Cervical Cancer

描述（由申请人提供）：人乳头瘤病毒（HPV）感染宫颈通常是自限性的，但它可以发展为宫颈癌，每年全世界约有273,500名妇女死于宫颈癌。即使在美国，宫颈癌也是15-34岁妇女癌症死亡的第三大常见原因，在平均寿命损失中排名第四，它对少数群体和社会经济地位低的妇女的影响尤为严重。流行病学研究表明，遗传因素占宫颈癌风险变异的27%左右。通过使用基于家族的对照的候选基因方法，我们已经确定了宿主基因组中与疾病进展相关的变异。许多关联在浸润性宫颈癌（ICC）的妇女亚组中更强，这些妇女感染了高危HPV 16型、18型和相关亚型。为了加速发现与子宫颈癌发展有关的遗传因素，我们提出了三个具体目标。目的1将验证参与宫颈癌发生的候选基因，并通过全基因组关联研究确定新的疾病单核苷酸多态性（snp）。在本研究的第一阶段，我们将使用500名无血缘关系的ICC白人女性（之前收集的）和2000名从公开的基因分型对照数据库中确定的白人女性人群作为病例对照样本。在第二阶段，我们将研究第二个独立的病例对照集（类似于第一个），以验证从动机良好的候选基因列表中确定的1000个snp和来自全基因组关联研究的前5000个hit。在统计分析中，我们将把第一阶段和第二阶段的数据结合起来。在目标2中，我们将探索易感snp之间的相互作用，并在1000例病例和4000例对照中进行亚组分析。异质性将探讨在不同亚群的情况下，如HPV类型，年龄诊断，和组织学。在Aim 3中，将在其他少数群体中验证显示与ICC最显著关联的snp，使用来自非裔美国人家族三组ICC和原位疾病的DNA样本以及患有ICC/CIN 3的西班牙裔妇女队列。这项研究将使我们能够在经济地利用现有资源的同时验证对ICC的易感性标记。确定宿主DNA的变异如何影响妇女对宫颈癌的易感性是很重要的，原因有几个。首先，这样的研究可以发现遗传标记，以识别患这种疾病的高风险妇女。其次，它们可以揭示人体在HPV感染后如何自我防御，这可能为疫苗设计或药物开发提供新的策略。最后，一个数据库和相应的ICC病例的血液样本和肿瘤以及家庭成员的DNA将是未来研究的宝贵资源。

DESCRIPTION (provided by applicant): Human papillomavirus (HPV) infection of the cervix is usually self-limiting, but it can progress to cervical cancer, which kills ~273,500 women each year worldwide. Even in the United States, cervical cancer is the third most common cause of cancer death in women aged 15-34 ranks fourth for average years of life lost, and it disproportionately affects minority groups and women of low socioeconomic status. Epidemiologic studies suggest that heritability accounts for ~27% of the variation in the risk for cervical tumors. Through a candidate gene approach that used family-based controls, we have identified variations in the host genome that associate with disease progression. Many associations are stronger in a subgroup of women with invasive cervical cancer (ICC) who are infected by the high-risk HPV types 16, 18, and related subtypes. To accelerate the discovery of genetic factors involved in the development of cervical cancer, we propose three specific aims. Aim 1 will validate candidate genes involved in cervical carcinogenesis and identify novel single nucleotide polymorphisms (SNPs) of disease, using a genome-wide association study. In stage 1 of this Aim, we will use a case-control sample of 500 unrelated Caucasian women with ICC (collected previously) and 2000 Caucasian female population controls identified from publicly available genotyping control databases. In stage 2, we will investigate a second independent case-control set (similar to the first) to validate 1000 SNPs identified from the list of well-motivated candidate genes and the top ~5000 hits from the genome-wide association study. In the statistical analysis, we will combine the stage 1 and stage 2 data. In Aim 2 we will explore interactions among susceptible SNPS and perform subgroup analysis among the 1000 cases and 4000 controls. Heterogeneity will be explored in various subsets of cases such as HPV type, age at diagnosis, and histology. The SNPs that show the most significant associations with ICC will be validated in other minority groups in Aim 3, using DNA samples from African American family-based trios of ICC and in situ disease and a cohort of Hispanic women with ICC/CIN 3. This study will enable us to validate markers of susceptibility to ICC while using available resources economically. Determining how variations in host DNA influence women's vulnerability to cervical cancer is important for several reasons. First, such studies could uncover genetic markers for identifying women who are at high risk for developing the disease. Second, they could reveal how the body defends itself after HPV infection, which might suggest new strategies for vaccine design or drug development. Finally, a database and corresponding blood samples and tumors from cases of ICC and DNA from family members would be an invaluable resource for future studies.