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

项目摘要/摘要 尽管有效地实施了抗逆转录病毒疗法(ART)方案，但撒哈拉以南非洲的个人 即使在艾滋病毒-1病毒载量完全被抑制的情况下，仍有几种肿瘤疾病的风险增加。 合并症、免疫缺陷、诊断和治疗机会不足、晚期疾病 临床表现、可用的治疗方式和社会经济状况是已知的影响癌症的因素。 生死存亡。眼表鳞状细胞瘤(OSSN)是眼部最常见的肿瘤，已成为一种 赞比亚艾滋病毒流行的高度流行的肿瘤表现。晚期疾病与 永久性视力受损、疾病进展和复发的严重风险通常如下 外科手术切除。因为HIV-1可能影响肿瘤生长的炎性驱动因素或形成局部组织 我们的总体目标是确定一些因素，如HPV合并感染，这些因素可能 与HIV-1感染者OSSN的发病机制不同。项目假设是 HIV-1混合感染促进了特定HPV基因类型的感染，这与发病率增加相关 OSSN。为了测试这一概念，项目组将确定一组赞比亚艾滋病毒-1阳性和 OSSN阴性患者的HIV-1疾病参数、OSSN组织病理学分级和 社会人口学职业和医疗风险因素。团队将通过以下方式来描述队列的特征 对口腔扁平苔藓不同阶段HPV存在的深入分子研究 HPV混合感染与HIV感染的相关性。它还将通过以下途径调查人乳头瘤病毒的病因学作用 病毒诱导的肿瘤标志物如p16，p53和YAP的定量，以及表征 人乳头瘤病毒在OSSN分级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进行分型 与OSSN相关，以确定是否存在驱动OSSN和 按年级或HIV-1混合感染进行隔离。这项研究将提供良好的培训和能力建设 为赞比亚年轻的癌症研究人员提供机会，同时阐明HPV的潜在作用 在OSSN中，通过揭示负责的基因(S)和肿瘤中调控失调的分子途径 纸巾。通过这项研究转让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记物，包括影响预防和治疗的标记物 赞比亚的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.