Epigenetic biomarkers of Cervical HPV in women with oral and oropharyngeal HPV, precancer and cancer

摘要 本申请是为了回应被确认为非CA-CA的特殊利益通知(NOSI)而提交的 23-038.人乳头瘤病毒(HPV)是全球最常见的性传播感染，有近 所有在有生之年感染的性行为活跃的女性和男性。人乳头瘤病毒感染在撒哈拉以南地区高度流行 非洲(SSA)，由于缺乏广泛的HPV疫苗接种。感染人乳头瘤病毒株，主要是HPV16和18型 大多数宫颈癌(~99%)和口腔和口咽癌(85-96%的鳞状细胞癌)都是由这种细菌引起的 品种)。由于缺乏HPV疫苗接种和宫颈癌，SSA的HPV相关癌症迅速增加 癌症筛查计划，如高收入国家(HIC)，如美国，以及 艾滋病毒/艾滋病。感染高危HPV(hr-HPV)，主要是HPV16和18型，导致口腔潜在恶性 疾病(OPMD)，口腔和口咽癌的癌前阶段。与宫颈癌不同 (Cc)即使在高收入国家，也没有完善的人口层面的OOPC筛查方案 (人类免疫缺陷病毒)，如美国。表观遗传变化是癌症的标志，表观遗传生物标志物代表 具有尚未开发的潜力的领域，用于识别因接触致癌物而有进展风险的妇女，例如 HrHPV感染，到癌前病变，最终到浸润性癌症。现在，没有普遍的筛查 与宫颈癌相比，口腔或口咽癌妇女的治疗策略。重要的是要采取行动 正在进行的R01赠款的优势：口腔HPV和相关口腔/口咽癌的表观遗传学 尼日利亚艾滋病毒携带者“(EpOCH)的研究，以确定可能也有高风险的妇女- 在同一时间(同步一致性)或在不久的将来(异步)存在宫颈HPV风险 协调性)。该项目的目标是：1)在西北大学进行宫颈拭子表观遗传学分析 两组妇女：口服hrHPV和宫颈HPV(n=30，第1组)与仅口服hrHPV(n=30，第2组)至 确定宫颈hrHPV相关dNaM生物标记物也可见于口腔和口咽部位。我们会比较一下 宫颈拭子(将在本补充材料中描述)和口腔拭子(已获得)的表观遗传学特征 在父R01项目R01CA27495201中)；和2)验证宫颈中hrHPV相关的生物标志物 目标1中确定的基因特异性dNaM聚合酶链式反应技术。这项验证将在伊巴丹大学进行， 尼日利亚。我们这项有指导的研究的长期目标是开发生物标志物或工具来筛选或 确定感染了hrHPV的妇女，这些感染可能会持续下去，并在未来发展为宫颈癌。这位导师 研究补充将培训申请者，星期日Oyerinde，MBBS，以获得新的技能和专门知识的学习 分子流行病学项目的设计，表观基因组的处理和分析，新的分析方法的开发， 道德和经济上合理的研究技术，以及同行评议和拨款的写作。

Summary This application is being submitted in response to the Notice of Special Interest (NOSI) identified as NOT-CA- 23-038. Human Papillomavirus (HPV) is the most common sexually-transmitted infection worldwide, with nearly all sexually active women and men infected during their lifetime. HPV infection is highly prevalent in Sub-Saharan Africa (SSA), due to the lack of widespread HPV vaccination. Infection of hr-HPV strains, mainly HPV 16 and 18 strains, accounts for most cervical cancer (~99%) and oral and oropharyngeal cancer (85-96% of squamous cell variety). HPV associated cancers are rapidly increasing in SSA due to lack of HPV vaccination and cervical cancer screening programs like high income countries (HICs), such as U.S., as well as high prevalence of HIV/AIDS. Infection with high-risk HPV (hr-HPV), mainly HPV 16 and 18, leads to oral potentially malignant disorders (OPMD), the precancerous stage of oral and oropharyngeal cancers (OOPCs). Unlike cervical cancer (CC) there are no well-developed, population-level screening programs for OOPC, even in high income countries (HICs) such as the U.S. Epigenetic changes are a hallmark of cancer, and epigenetic biomarkers represent a field with untapped potential for identifying women at risk of progression from exposure to carcinogens, such as hrHPV infection, to pre-malignancy, and ultimately to invasive cancers. Now, there is no universal screening strategy for women with oral or oropharyngeal cancer compared to cervical cancer. It is important to take advantage of the ongoing R01 grant “Epigenetics of oral HPV and associated oral/oropharyngeal cancer in people living with HIV in Nigeria” (EpOOCH) study to identify women that might also be at risk of having high- risk HPV in the cervix at the same time (synchronous concordance) or in the nearest future (asynchronous concordance). The aims of this project are: 1) To conduct cervical swab epigenetic profiling (at Northwestern) in two groups of women: oral hrHPV and cervical HPV (n=30, Group 1) vs. oral hrHPV only (n=30, Group 2) to identify cervical hrHPV-associated DNAm biomarkers also seen in oral and oropharyngeal sites. We will compare epigenetic profile in both cervical swab (will be profiled by this supplement) and oral swab (have been obtained in the parent R01 project R01CA27495201); and 2) To validate the hrHPV-associated biomarkers in cervix using gene-specific DNAm PCR technology identified in Aim 1. This validation will be performed at University of Ibadan, Nigeria. Our long-term goal for this mentored research is to develop biomarkers or tools that can screen or identify women with hrHPV infections that could persist and develop into cervical cancer in future. This mentored research Supplement will train the applicant, Sunday Oyerinde, MBBS, to gain new skills and expertise in study design of molecular epidemiology projects, epigenomic processing and analysis, new assay development, ethical and economically sound research techniques, and writing for peer review and grants.