Genetic Susceptibility to Cervical Cancer

宫颈癌的遗传易感性

• 批准号: 6750069
• 负责人: Janet S. Rader
• 金额: $ 33.67万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6750069
• 关键词: cervix neoplasms; clinical research; family genetics; female; gene frequency; genetic markers; genetic screening; genetic susceptibility; human genetic material tag; human papillomavirus; human subject; linkage disequilibriums; neoplasm /cancer genetics; phlebotomy; questionnaires; serotyping; single nucleotide polymorphism; virus related neoplasm /cancer

DESCRIPTION (provided by applicant): Cervical cancer kills more than 200,000 people each year worldwide, disproportionately affecting women of low socioeconomic status. Infection with high-risk human papillomavirus (HPV) is the main causal factor, but additional factors must be involved because only a small proportion of HPV-infected women develop cancer. Epidemiologic studies suggest that some predisposing factors are genetic heritability accounts for about 27 percent of the total variation in liability to cervical tumor development. Because the responsible genes (or gene variants) have not been uncovered, it is not yet possible to develop methods for identifying the small proportion of women with preinvasive cervical intraepithelial neoplasia (CIN) who will need treatment. To address this deficit, we plan to identify markers that associate with cervical cancer. Such markers might also be useful for screening women in the general population. To elucidate the role of genetic factors in the development of cervical cancer, we will study DNA from women who have invasive cervical cancer (ICC) or CIN III and are also infected with high risk HPV subtypes. We will select candidate genes that appear critical for the development of the cancer, including the HLA DQB1/DRB1 locus and other immune markers, genes that are cellular targets of HPV E6, E7, and E5 oncoproteins, and genes implicated in the progression of cervical neoplasia. Within each gene, we will focus on small variations, such as differences in single bases. Such single nucleotide polymorphisms (SNPs) are the most common genetic variations among individuals, accounting for a substantial proportion of phenotypic variability. We will evaluate their influence on interactions between HPV and cervical cells by using the transmission/disequilibrium test (TDT). Unlike the case-control method, the TDT assesses associations between specific alleles and disease endpoints without being vulnerable to errors caused by stratification of genetically disparate populations or undiagnosed preclinical disease in "controls.'" We will test each variation for association with ICC or CIN Ill by comparing frequency distributions of patient alleles (cases) with those of nontransmitted parental 'alleles, which provide a perfect ethnically matched control sample. If a polymorphism is inherited with higher-than-Mendelian frequency by the women with ICC or CIN III, we will suspect that variant of predisposing HPV-infected women to cervical cancer. Subsequent case control and cohort studies could then confirm the association. This investigative sequence is much more cost-effective than population studies that begin without first identifying potentially culpable genes. Determining how small variations in host DNA influence vulnerability to cervical cancer is critical to understanding the pathogenesis of the disease and therefore to the development of superior screening and diagnostic tests. As the field of pharmacogenetics expands, this information might enable vaccine and drug developers to tailor their products to "cervical cancer genotypes."

描述（由申请人提供）：宫颈癌每年在全球范围内杀死超过200,000人，对社会经济状况低下的妇女的影响不成比例。高危人乳头瘤病毒（HPV）的感染是主要因果因素，但必须涉及其他因素，因为只有一小部分HPV感染的妇女患癌症。流行病学研究表明，某些诱发因素是遗传性遗传力，约占宫颈肿瘤发育责任总责任的27％。由于尚未发现负责任的基因（或基因变异），因此尚不可能开发出识别需要治疗的上皮前肿瘤前肿瘤（CIN）的少数方法的方法。为了解决这一赤字，我们计划确定与宫颈癌相关的标记。这样的标记也可能对筛查一般人群的妇女有用。为了阐明遗传因素在宫颈癌发展中的作用，我们将研究患有侵袭性宫颈癌（ICC）或CIN III的女性的DNA，并且还感染了高风险HPV亚型。我们将选择对癌症发展至关重要的候选基因，包括HLA DQB1/DRB1基因座和其他免疫标记，是HPV E6，E7和E5癌蛋白的细胞靶标的基因，以及与宫颈肿瘤进展有关的基因。在每个基因中，我们将专注于较小的变化，例如单个碱基的差异。这种单核苷酸多态性（SNP）是个体中最常见的遗传变异，占表型变异性的很大比例。我们将使用传输/不平衡测试（TDT）评估它们对HPV和宫颈细胞之间相互作用的影响。 Unlike the case-control method, the TDT assesses associations between specific alleles and disease endpoints without being vulnerable to errors caused by stratification of genetically disparate populations or undiagnosed preclinical disease in "controls.'" We will test each variation for association with ICC or CIN Ill by comparing frequency distributions of patient alleles (cases) with those of nontransmitted parental 'alleles, which provide a perfect ethnically matched控制样本。如果具有ICC或CIN III的女性以比孟德尔的频率高于孟德尔的频率，我们将怀疑诱发HPV感染的女性患有宫颈癌的变体。随后的病例控制和队列研究可以确认关联。该调查序列比首先识别潜在的可屈服基因的人群研究比人口研究更具成本效益。确定宿主DNA的较小变化如何影响宫颈癌的脆弱性对于理解疾病的发病机理，因此对于出色的筛查和诊断测试的发展至关重要。随着药物遗传学领域的扩展，此信息可能使疫苗和药物开发人员能够为“宫颈癌基因型”量身定制其产品。