Genetic Susceptibility to Cervical Cancer

描述(申请人提供)：全球每年有20多万人死于宫颈癌，对社会经济地位较低的妇女影响更大。感染高危人乳头瘤病毒(HPV)是主要原因，但必须涉及其他因素，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，一些易感因素是遗传易感性，约占宫颈癌发生的总变异的27%。由于责任基因(或基因变异)尚未被发现，目前还不可能开发出方法来识别需要治疗的一小部分侵袭前宫颈上皮内瘤变(CIN)妇女。为了解决这一缺陷，我们计划确定与宫颈癌相关的标志物。这些标记物也可能对普通人群中的妇女进行筛查。为了阐明遗传因素在宫颈癌发生发展中的作用，我们将研究患有浸润性宫颈癌(ICC)或CIN III并同时感染高危HPV亚型的妇女的DNA。我们将选择与癌症发生密切相关的候选基因，包括HLADQB1/DRB1基因座和其他免疫标志物，作为HPVE6、E7和E5癌蛋白细胞靶点的基因，以及与宫颈肿瘤进展有关的基因。在每个基因中，我们将专注于微小的变异，例如单碱基的差异。这种单核苷酸多态(SNPs)是个体间最常见的遗传变异，占表型变异的很大比例。我们将通过传递/不平衡检验(TDT)来评估它们对HPV与宫颈细胞相互作用的影响。与病例对照方法不同，TDT评估特定等位基因与疾病终点之间的关联，而不容易受到“对照”中遗传差异人群的分层或未诊断的临床前疾病造成的错误的影响。我们将通过比较患者等位基因(病例)和未传播的父母等位基因的频率分布来测试每个变异与ICC或CIN Ill的关联，这提供了一个完美的种族匹配对照样本。如果ICC或CIN III的女性以高于孟德尔频率的频率遗传一种多态，我们将怀疑该变异导致HPV感染的女性患宫颈癌。随后的病例对照和队列研究可以证实这种联系。这种调查序列比没有首先确定潜在罪魁祸首的人群研究更具成本效益。确定宿主DNA的微小变异如何影响对宫颈癌的易感性，对于了解疾病的发病机制，从而开发更好的筛查和诊断测试至关重要。随着药物遗传学领域的扩大，这些信息可能会使疫苗和药物开发商能够根据“宫颈癌基因类型”定制他们的产品。

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."