Genetic Susceptibility to Cervical Cancer

宫颈癌的遗传易感性

• 批准号: 7238730
• 负责人: Janet S. Rader
• 金额: $ 29.75万
• 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 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7238730
• 关键词: 3' Untranslated Regions; Accounting; Address; Affect; Alleles; Biological; Biopsy; Blood specimen; CDKN1A gene; Candidate Disease Gene; Case-Control Studies; Cells; Cervical; Cervical Intraepithelial Neoplasia; Cervix Neoplasms; Cohort Studies; Cyclin A; Cyclin E; DNA; DNA Fingerprinting; Databases; Development; Diagnostic tests; Disease; Disease Progression; End Point; Epidemiologic Studies; Epidermal Growth Factor Receptor; Exons; FOS gene; Family; Family member; Frequencies; Gene Frequency; General Population; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genomics; Genotype; Goals; HPV-High Risk; Heritability; High Pressure Liquid Chromatography; Human Papillomavirus; Human papillomavirus 16; IRF3 gene; Immune response; Immunologic Markers; Individual; Infection; Inherited; Invasive; JUN gene; Laboratories; Linkage Disequilibrium; MTHFR gene; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Methods; Methylenetetrahydrofolate reductase (NADPH); Neoplasms; Nucleic Acid Regulatory Sequences; Numbers; Oncogene Proteins; PTGS2 gene; Papillomavirus; Parents; Pathogenesis; Patients; Pharmaceutical Preparations; Pharmacogenetics; Polymerase Chain Reaction; Population; Population Study; Predisposing Factor; Predisposition; RCN2 gene; Recruitment Activity; Role; Sampling; Score; Screening procedure; Single Nucleotide Polymorphism; Specimen; Stratification; Structure; TAP2 gene; TP53 gene; Testing; Transcription Factor AP-1; Triad Acrylic Resin; Vaccines; Variant; Viral; Woman; base; carcinogenesis; case control; cellular targeting; cost; design; gene function; human RCN2 protein; killings; low socioeconomic status; oncoprotein p21; p27 Cell Cycle Protein; p27 Enzyme Inhibitor; paxillin; pre-clinical; size; transmission process; tumor

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）：全世界每年有超过 200,000 人死于宫颈癌，其中社会经济地位较低的女性受到的影响尤为严重。高危型人乳头瘤病毒（HPV）感染是主要致病因素，但还必须涉及其他因素，因为只有一小部分感染 HPV 的女性会患上癌症。流行病学研究表明，一些诱发因素是遗传性，约占宫颈肿瘤发展总变异的 27%。由于尚未发现相关基因（或基因变异），因此尚不可能开发出方法来识别一小部分需要治疗的患有浸润性宫颈上皮内瘤变 (CIN) 的女性。为了解决这一缺陷，我们计划识别与宫颈癌相关的标记物。这些标记也可能有助于筛查一般人群中的女性。为了阐明遗传因素在宫颈癌发展中的作用，我们将研究患有浸润性宫颈癌 (ICC) 或 CIN III 且感染高危 HPV 亚型的女性的 DNA。我们将选择对癌症发展至关重要的候选基因，包括 HLA DQB1/DRB1 位点和其他免疫标记物、HPV E6、E7 和 E5 癌蛋白的细胞靶标基因，以及与宫颈肿瘤进展有关的基因。在每个基因中，我们将关注微小的变化，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，占表型变异的很大一部分。我们将使用传播/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。与病例对照方法不同，TDT 评估特定等位基因和疾病终点之间的关联，而不易受到因遗传不同群体分层或“对照”中未诊断的临床前疾病而导致的错误。我们将通过比较患者等位基因（病例）与非传播父母“等位基因”的频率分布来测试每种变异与 ICC 或 CIN Ill 的关联，这提供了完美的种族匹配 控制样品。如果患有 ICC 或 CIN III 的女性遗传的多态性频率高于孟德尔频率，我们将怀疑该变异使 HPV 感染的女性易患宫颈癌。随后的病例对照和队列研究可以证实这种关联。这种调查顺序比在没有首先识别潜在罪魁祸首的情况下开始的群体研究更具成本效益。确定宿主 DNA 的微小变异如何影响宫颈癌的易感性对于了解该疾病的发病机制至关重要，因此对于开发高级筛查和诊断测试至关重要。随着药物遗传学领域的扩展，这些信息可能使疫苗和药物开发商能够根据“宫颈癌基因型”定制他们的产品。