Epigenetic study of oral HPV infection-associated oral cancer in people living with HIV in Nigeria

项目摘要/摘要 该项目的长期目标是a)了解人乳头瘤病毒(HPV)的流行病学- 与口腔和口咽癌(OOPC)相关的艾滋病毒携带者(PLWH)以及 OOPC中的表观遗传生物标志物，以及b)开发潜在的有针对性的干预措施，以改善预防和治疗 早期发现OOPC。全球约5%的癌症是由HPV引起的，其中OOPC的比例越来越高； 我们最近的数据显示，17%的OOPC样本有HPV感染。这一日益恶化的公共卫生问题 在艾滋病毒高流行率的国家，如尼日利亚，情况更加严重。艾滋病毒感染对人类健康的影响 免疫功能障碍促进致癌性HPV联合感染的传播和重新激活。艾滋病毒-人乳头瘤病毒联合 感染会协同增加口腔潜在恶性疾病(OPMD)的患病率， PLWH患者进展为OOPC的危险。由于艾滋病毒是通过抗逆转录病毒疗法(ART)控制的，PLWH 患有慢性炎症和持续免疫缺陷的人寿命更长，使他们更容易患上 HPV感染及其致癌后果。表观遗传生物标记物代表了一个尚未开发的领域 有可能确定HPV感染的PLWH有发展为侵袭性OOPC的风险。DNA甲基化 (DNaM)修饰是包括OOPC在内的癌症中一种被充分研究的表观遗传学机制。DNaM修改 可由外源性因素诱发，包括艾滋病毒和人乳头瘤病毒感染及其相关癌症。各国 如尼日利亚提供了独特的资源和机会来研究PLWH中HPV相关的癌症，特别是 OPMDs向恶性OOPC进展的纵向研究。我们推测口腔HPV感染 可能诱导PLWH的dNaM改变，其中一些可能是OOPC发生发展的机制。这样的变化 可能因HPV亚型不同而不同，并可在预测进展为侵袭性OOPC的OPMD中看到。我们计划 检测4组HIV阳性患者的组织特异性表观遗传标志物：1)HPV(+)OOPC(n=150)； HPV(-)OOPC 150例，HPV(+)伴良性疣100例，HPV(+)伴OPMDs 400例。招聘 将于#年在伊巴丹大学医学院/大学学院医院(COMUI/UCH)进行 尼日利亚、西非以及其他10个医院卫星招聘网站。COMUI/UCH是最大的辐射 尼日利亚的肿瘤学转诊网站和该地区领先的肿瘤学服务中心之一。我们还将 研究来自同一地区现有队列(SHINI)的HIV(-)OOPC患者。我们的主要目标是 为了：1)了解PLWH中HPV相关OOPC的流行病学；2)确定HPV的dNaM生物标志物- PLWH中相关的OOPC；以及3)检测OOPC侵袭性和OPMD的dNaM生物标志物 随访过程中的进展。我们的研究团队有着长期和成功的合作记录， 西北大学MPIs拥有在PLWH研究HPV相关性宫颈癌的丰富经验 通过NCI资助的尼日利亚U54财团。

PROJECT SUMMARY/ABSTRACT The long-term goals of this project are to a) understand the epidemiology of Human papillomavirus virus (HPV)- associated oral and oropharyngeal cancers (OOPC) among people living with HIV (PLWH) as well as the role of epigenetic biomarkers in OOPC, and b) to develop potential targeted interventions to improve prevention and early detection of OOPC. HPV causes ~5% of cancers worldwide, including an increasing proportion of OOPCs; our recent data showed that 17% of OOPC samples have HPV infections. This worsening public health problem is even more serious in countries with high HIV prevalence, such as Nigeria. The impact of HIV infection on immune dysfunction promotes transmission and reactivation of oncogenic HPV co-infections. HIV-HPV co- infection then synergistically increases the prevalence of oral potentially malignant disorders (OPMDs), and the hazards of progression to OOPC among PLWH. As HIV is controlled with antiretroviral therapy (ART), PLWH live longer with chronic inflammation and continued immunodeficiency, making them even more susceptible to HPV infection and its cancer-promoting consequences. Epigenetic biomarkers represent a field with untapped potential for identifying HPV-infected PLWH who are at risk of progression to invasive OOPC. DNA methylation (DNAm) modifications are a well-studied epigenetic mechanism in cancer including OOPC. DNAm modifications are inducible by exogenous factors, including HIV and HPV infection and their associated cancers. Countries like Nigeria provide unique resources and opportunities to study HPV-associated cancers in PLWH, particularly longitudinal studies of the progression of OPMDs into malignant OOPCs. We hypothesize that oral HPV infection may induce DNAm changes in PLWH, some of which are mechanisms in OOPC development. Such changes may differ by HPV subtype, and can be seen in OPMDs that predict the progression to invasive OOPC. We plan to examine tissue-specific epigenetic biomarkers in 4 groups of HIV(+) patients: 1) HPV(+) OOPC (n=150); 2) HPV(-) OOPC (n=150); 3) HPV(+) with benign warts (n=100), and 4) HPV(+) with OPMDs (n=400). Recruitment will be conducted at the College of Medicine, University of Ibadan/University College Hospital (COMUI/UCH) in Nigeria, West Africa as well as 10 other hospital satellite recruitment sites. COMUI/UCH is the largest radiation oncology referral site in Nigeria and one of the leading centers for oncological services in the region. We will also study HIV (-) OOPC patients derived from our existing cohort (SHINI) in the same area. Our primary Aims are to: 1) Understand the epidemiology of HPV-associated OOPCs in PLWH; 2) Identify DNAm biomarkers of HPV- associated OOPCs in PLWH; and 3) Examine DNAm biomarkers for OOPC aggressiveness and OPMD progression during follow up. Our research team has a long and successful collaboration record and the Northwestern University MPIs have extensive experience studying HPV-associated cervical cancer in PLWH through an NCI-funded U54 consortium in Nigeria.