Nonhomologous end-joinging polymorphisms and HPV integration in cervical dysplasi

描述（由申请人提供）：项目总结/摘要宫颈癌是全球女性死亡的第二大原因。人乳头瘤病毒（HPV）是宫颈癌的主要致病因子。分子生物学研究表明，高危型HPV整合到宿主细胞的基因组中，并能够破坏许多导致细胞增殖失控的信号转导途径。虽然我们对持续性感染的生物学了解很多，但对以下方面了解甚少：1）导致一些HPV暴露女性感染HPV并发展癌前病变或癌性病变的因素，2）导致其他HPV暴露女性迅速清除感染而无后遗症的因素。与预测HPV整合和宫颈癌进展相关的一个尚未得到充分研究的领域是由于关键遗传途径中的遗传变异而导致的潜在易感性。该领域的主要研究集中在与HPV感染相关的遗传变异上，但很少有人关注可能与整合相关的途径。因此，本申请的目的是检查相关DNA修复途径中的多态性对宫颈细胞学正常的女性和低度或高度鳞状上皮内病变的女性中HPV病毒整合的影响。我们的假设是，具有非同源末端连接DNA修复途径中基因的风险等位基因的女性具有更大的HPV整合到宿主细胞基因组中的潜力，从而诱导更大的染色体不稳定性，并且这些“易感”女性更有可能出现高级别病变或宫颈癌。这一目标将通过三个具体目标来实现：（1）确定与具有正常宫颈细胞学的那些相比，具有低度和高度上皮内病变的女性中的非同源末端连接（NHEJ）DNA修复途径中的多态性的等位基因频率的差异; 2）确定与具有正常宫颈细胞学的那些相比，具有低度和高度上皮内病变的女性中存在的病毒整合量的差异;和3）通过宫颈发育不良的临床结果确定NHEJ基因型和病毒整合之间的关联（例如，正常、LSIL、HSIL）。 公共卫生相关性：宫颈癌是全球女性死亡的第二大原因，宫颈癌前病变每年为与其筛查和治疗相关的医疗保健费用贡献数十亿美元。知识上的主要差距与导致一些接触HPV的女性感染HPV并出现癌前病变或癌性病变的因素有关，而另一些女性则迅速清除感染而没有后遗症。有了这些信息，就可以根据妇女的个人风险状况制定更好的公共卫生筛查方案。

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Cervical cancer is the second leading cause of death in women worldwide. Human papillomavirus (HPV) is the primary causal agent for cervical cancer. Molecular biologic studies have demonstrated that the high-risk HPV types integrate into the genome of the host cell and are able to disrupt numerous signal transduction pathways that lead to uncontrolled cellular proliferation. While we know quite a bit about the biology of the persistent infections, little is understood about: 1) the factors that cause some HPV-exposed women to become HPV-infected and develop precancerous or cancerous lesions, nor 2) the factors that cause other HPV-exposed women to clear the infection rapidly with no sequelae. One area related to prediction of HPV integration and cervical cancer progression that has not been well- studied is the potential susceptibility due to genetic variation in key genetic pathways. The primary studies in this area have focused on genetic variation related to HPV infection, but few have focused on the pathways that could be related to integration. Therefore, the goal of this application is to examine the effects of polymorphisms in a pertinent DNA repair pathway on HPV viral integration in women with normal cervical cytology and those with low-grade or high-grade squamous intraepithelial lesions. Our hypothesis is that women with risk alleles for genes in the non-homologous end-joining DNA repair pathway have greater potential for HPV to integrate into the host cell genome inducing greater chromosome instability and that these "susceptible" women are more likely to present with high-grade lesions or cervical cancer. This goal will be accomplished through three specific aims: 1.) Determine differences in allele frequency for polymorphisms in the non-homologous end-joining (NHEJ) DNA repair pathway among women with low-grade and high-grade intraepithelial lesions compared to those with normal cervical cytology; 2) Determine difference in the amount of viral integration present among women with low-grade and high- grade intraepithelial lesions compared to those with normal cervical cytology; and 3) Determine the association between the NHEJ genotypes and viral integration by clinical outcome of cervical dysplasia (e.g., normal, LSIL, HSIL). PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Cervical cancer is the second leading cause of death in women worldwide, and cervical precancerous lesions contribute billions of dollars per year to health care costs related to their screening and treatment. The main gap in knowledge is related to the factors that cause some HPV-exposed women to become HPV-infected and develop precancerous or cancerous lesions while others clear the infection rapidly with no sequelae. Given this information better public health screening programs could be tailored to a woman's individual risk profile.