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

项目概要/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- 艾滋病毒感染者（PLWH）中相关的口腔和口咽癌（OOPC）以及 OOPC中的表观遗传生物标志物，和B）开发潜在的靶向干预措施以改善预防和 早期发现OOPC。HPV导致全球约5%的癌症，包括越来越多的OOPC; 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 在尼日利亚等艾滋病毒流行率高的国家，情况更加严重。艾滋病毒感染对 免疫功能障碍促进致癌HPV合并感染的传播和再活化。HIV-HPV共 感染然后协同增加口腔潜在恶性疾病（OPMD）的患病率，并且 在PLWH中进展为OOPC的风险。由于艾滋病毒是通过抗逆转录病毒疗法控制的， 慢性炎症和持续免疫缺陷的寿命更长，使他们更容易受到 HPV感染及其促癌后果表观遗传生物标志物代表了一个尚未开发的领域， 有可能识别HPV感染的PLWH，这些PLWH有进展为侵袭性OOPC的风险。DNA甲基化 DNA（DNAm）修饰是包括OOPC在内的癌症中研究充分的表观遗传机制。DNAm修饰 可由外源因素诱导，包括HIV和HPV感染及其相关癌症。国家 像尼日利亚这样的国家提供了独特的资源和机会来研究PLWH中HPV相关的癌症， OPMD进展为恶性OOPC的纵向研究。我们假设口腔HPV感染 可能导致PLWH中DNAm的变化，其中一些是OOPC发展的机制。这种变化 可能因HPV亚型而异，并且可以在预测侵袭性OOPC进展的OPMD中看到。我们计划 在4组HIV（+）患者中检查组织特异性表观遗传生物标志物：1）HPV（+）OOPC（n=150）; 2） HPV（-）OOPC（n=150）; 3）HPV（+）伴良性疣（n=100）; 4）HPV（+）伴OPMD（n=400）。招聘 将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个医院卫星招募站点。COMUI/UCH是最大的辐射 该中心是尼日利亚的肿瘤转诊中心，也是该地区领先的肿瘤服务中心之一。我们还将 研究HIV（-）OOPC患者来自我们在同一地区的现有队列（SHINI）。我们的主要目标是 目的：1）了解PLWH中HPV相关OOPC的流行病学; 2）鉴定HPV的DNAm生物标志物- PLWH中相关的OOPC;和3）检查OOPC侵袭性和OPMD的DNAm生物标志物 在后续的进展。我们的研究团队有着长期成功的合作记录， 西北大学MPI在研究PLWH中HPV相关宫颈癌方面具有丰富的经验 通过国家癌症研究所资助的尼日利亚的U 54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.