Research Project 2: Pathological Diagnosis and Etiology of Ocular Surface Squamous Neoplasia in Zambia

项目总结/摘要 尽管抗逆转录病毒疗法（ART）计划得到有效实施，但撒哈拉以南非洲的个人 即使在HIV-1病毒载量被完全抑制的情况下，仍然存在几种肿瘤性疾病的增加风险。 合并症、免疫缺陷、诊断和治疗途径不足、晚期疾病 临床表现、可用的治疗方式和社会经济地位是影响癌症的已知因素 生存眼表鳞状细胞瘤（OSSN）是眼部最常见的肿瘤， 赞比亚艾滋病毒流行病的高度流行的肿瘤表现。晚期疾病与 在以下情况下，永久性视力损害、疾病进展和复发的风险很高 手术切除因为HIV-1可能影响肿瘤生长的炎症驱动因素或形成局部组织， 我们的总体目标是确定可能导致眼组织中HPV感染的因素，如HPV合并感染， 与HIV-1感染个体中OSSN的发病机制差异相关。项目假设 HIV-1合并感染促进了特定HPV基因型的感染，这与增加的发病率相关， OSSN的。为了检验这一概念，项目小组将对一组赞比亚HIV-1阳性和 HIV-1疾病参数、OSSN组织病理学分级为阴性的OSSN患者，以及 社会人口学职业和医疗风险因素。该团队将通过以下方式跟踪队列的表征： 对OSSN瘤形成的各个阶段中HPV存在的深入分子研究， HPV合并感染与HIV感染的关系。它还将调查HPV的病因作用， 病毒诱导的肿瘤标志物（例如p16、p53和雅普）的定量，以及表征 HPV在分级OSSN肿瘤中的基因组整合状态。最后，该团队将对检测到的所有HPV进行基因分型 与OSSN相关，以确定是否存在驱动OSSN的特定HPV基因型， 按年级隔离，或按HIV-1合并感染隔离。这项研究将提供极好的培训和能力建设， 为年轻的赞比亚癌症研究人员提供机会，同时阐明HPV的潜在作用 在OSSN中，通过揭示肿瘤中负责的基因型和失调的分子途径， 组织中通过这项研究转移分子诊断方法和专业知识可能会导致 开发新的预后和诊断标志物，包括影响预防和治疗的标志物 OSSN或其他恶性肿瘤。

PROJECT SUMMARY/ABSTRACT Despite effective implementation of anti-retroviral therapy (ART) programs, individuals in sub-Saharan Africa remain at increased risk for several neoplastic diseases even when HIV-1 viral load is fully suppressed. Comorbidities, immunodeficiency, inadequate diagnosis and treatment access, advanced disease presentation, available treatment modalities, and socio-economic status are factors known to impact cancer survival. Ocular surface squamous neoplasia (OSSN), the most common tumor of the eye, has emerged as a highly prevalent neoplastic manifestation of the HIV epidemic in Zambia. Advanced disease is associated with profound risk for permanent visual impairment, disease progression, and recurrence is common following surgical excision. Because HIV-1 could impact inflammatory drivers of neoplastic growth or form a local tissue reservoir in ocular tissue, our overall goal is to identify factors, such as HPV con-infection, that may differentially associate with the pathogenesis of OSSN in HIV-1 infected individuals. The project hypothesis is that HIV-1 co-infection promotes infection with specific HPV genotypes, which correlates with increased rates of OSSN. To test this concept, the project team will characterize a cohort of Zambian HIV-1 positive and negative OSSN patients with regard to their HIV-1 disease parameters, OSSN histopathological grading, and socio-demographic occupation and medical risk factors. The team will follow characterization of the cohort by an in-depth molecular investigation of the presence of HPV in the various stages of OSSN neoplasia, and any association of HPV co-infection with HIV infection. It will also investigate the etiological role of HPV through quantification of virally-induced tumor markers such as p16, p53 and YAP, as well as characterizing the genomic integration state of HPV in graded OSSN tumors. Finally, the team will genotype all HPVs detected in association with OSSN to determine whether there are specific HPV genotypes that drive OSSN and segregate by grade, or by HIV-1 co-infection. This study will provide an excellent training and capacity-building opportunity for young Zambian cancer researchers while simultaneously illuminating the potential role of HPV in OSSN by revealing both the genotype(s) responsible, and the molecular pathways dysregulated in tumor tissues. The transfer of molecular diagnostic methods and expertise through this study will likely lead to the development of new prognostic and diagnostic markers, including those that impact prevention and treatment of OSSN or other malignancies in Zambia.