Nonhomologous end-joinging polymorphisms and HPV integration in cervical dysplasi

项目摘要/摘要子宫颈癌是全球妇女死亡的第二大原因。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，能够破坏许多信号转导途径，导致不受控制的细胞增殖。虽然我们对持续感染的生物学有相当多的了解，但我们对以下方面知之甚少：1)导致一些暴露于hpv的妇女感染hpv并发展为癌前病变或癌前病变的因素；2)导致其他暴露于hpv的妇女迅速清除感染而没有后遗症的因素。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关键遗传途径中遗传变异的潜在易感性。该领域的初步研究主要集中在与HPV感染相关的遗传变异上，但很少关注可能与整合相关的途径。因此，本应用程序的目的是研究相关DNA修复途径多态性对宫颈细胞学正常和低级别或高级别鳞状上皮内病变女性HPV病毒整合的影响。我们的假设是，具有非同源末端连接DNA修复途径中基因风险等位基因的女性更有可能将HPV整合到宿主细胞基因组中，从而导致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：测定低级别和高级别上皮内病变妇女与宫颈细胞学正常妇女相比，非同源末端连接（NHEJ） DNA修复途径多态性等位基因频率的差异；2)与宫颈细胞学正常的妇女相比，确定低级别和高级别上皮内病变妇女中存在的病毒整合量的差异；3)确定NHEJ基因型与宫颈发育不良（如正常、LSIL、HSIL）临床结局的病毒整合之间的关系。

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.